J Cardiovasc Pharmacol. 2000 Jun;35(6):849-54.
Serotonin reuptake inhibitor fluoxetine decreases arteriolar myogenic tone by reducing smooth muscle [Ca2+]i.

Ungvari Z, Pacher P, Koller A.

Institute of Pathophysiology, Semmelweis University, Budapest, Hungary.

Previous studies showed that the serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine (Prozac) dilates skeletal muscle and cerebral arterioles independent of the endothelium. We hypothesized that fluoxetine affects the contractile activity of arteriolar smooth muscle by interfering with Ca2+ signaling pathways. The effects of fluoxetine on pressure-induced tone of isolated rat skeletal muscle arterioles (approximately 110 microm) were investigated by videomicroscopy. Changes in smooth muscle [Ca2+]i were measured simultaneously by the fura-2 ratiometric method. Elevation of intraluminal pressure (from 20 to 120 mm Hg) increased (by approximately 20%) the smooth muscle calcium fluorescence ratio (R(Ca)) and resulted in a significant myogenic constriction (approximately 40%). Fluoxetine and nifedipine significantly decreased R(Ca) (by approximately 30%) and abolished pressure-induced arteriolar tone (EC50, 3.1 x 10(-6) and 6.0 x 10(-9) M, respectively). Constrictions to the L-type Ca2+ channel opener Bay K 8644 also were inhibited and abolished by increasing doses of fluoxetine (3 x 10(-6) and 10(-5) M, respectively). In the presence of 10(-5) M fluoxetine, a concentration that elicited submaximal (approximately 80%) dilation, elevation of extracellular Ca2+ concentration (from 2.5 to 15 mM) normalized R(Ca) and restored arteriolar myogenic tone. Thus, fluoxetine reduces [Ca2+]i and tone of arteriolar smooth muscle, likely by interfering with Ca2+ entry. We speculate that the "calcium antagonist" effect of fluoxetine may be an additional element in the therapeutic actions of this drug.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10836717&dopt=Abstract fluoxetine




Neuropharmacology. 2000 Jul 10;39(9):1608-16.
The ability of WAY100,635 to potentiate the neurochemical and functional actions of fluoxetine is enhanced by co-administration of SB224,289, but not BRL15572.

Gobert A, Dekeyne A, Millan MJ.

Institut de Recherches Servier, Psychopharmacology Department, 125 Chemin de Ronde, 78290, Croissy-sur-Seine, France.

The present study employed a combined neurochemical and behavioural approach to address the question of whether blockade of (presynaptic) 5-HT(1B) or 5-HT(1D) receptors enhances the facilitatory influence of 5-HT(1A) autoreceptor antagonism upon the actions of selective serotonin re-uptake inhibitors (SSRI). In the presence of the selective 5-HT(1A) antagonist, WAY100,635, the fluoxetine-induced increase in dialysate levels of 5-HT in the frontal cortex (FCX) of freely-moving rats was significantly potentiated. The selective 5-HT(1B) antagonist, SB224,289, likewise potentiated the increase in 5-HT levels evoked by fluoxetine. Further, administered together, WAY100,635 and SB224,289, at least additively, potentiated the influence of fluoxetine upon 5-HT levels. This effect was selective inasmuch as, either alone or together, WAY100,635 and SB224,289 did not modify the influence of fluoxetine upon FCX levels of dopamine (DA) or noradrenaline (NA) quantified in the same dialysis samples. Co-administration of SB224,289 also enhanced the ability of WAY100,635 to potentiate the induction of head-twitches (HTW) by fluoxetine. This response reflects activation of 5-HT(2A) sites in FCX and was abolished by the selective 5-HT(2A) antagonist, MDL100,907. In contrast to SB224,289, the 5-HT(1D) antagonist, BRL15572, failed to enhance the facilitatory influence of WAY100,635 upon the neurochemical or behavioural actions of fluoxetine. In conclusion, co-joint blockade of 5-HT(1B) - but not 5-HT(1D) - with 5-HT(1A) autoreceptors markedly potentiates the neurochemical and functional actions of the SSRI, fluoxetine.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10854905&dopt=Abstract fluoxetine

war.wyeth.com

Using in vivo microdialysis in the frontal cortex of the freely moving rat we evaluated the effects of chronic treatment with the serotonin specific reuptake inhibitor (SSRI) fluoxetine in the presence and absence of the 5-HT(1A)/beta-adrenergic antagonist (+/-)pindolol. Chronic vehicle treated animals produced no significant response to a challenge with fluoxetine (10 mg kg(-1)) on day 8 and 15. Alternatively, a significant (P<0.05) decrease in extracellular 5-HT was observed in control animals upon challenge with the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.03 and 0.1 mg kg(-1)). Conversely, animals treated with fluoxetine (10 mg kg(-1) o.d.) for 7 and 14 days produced a significant (P<0.05) 2 fold increase in extracellular 5-HT when challenged with fluoxetine (10 mg kg(-1)) on day 8 and 15. Moreover, no significant decrease in extracellular 5-HT was observed upon challenge with either dose of 8-OH-DPAT. Animals chronically treated with (+/-)pindolol (10 or 20 mg kg(-1) b.i.d.) produced a significant dose-related increase in extracellular 5-HT upon challenge with fluoxetine on day 15 only. Furthermore, both doses produced a significantly blunted response to the low dose challenge of 8-OH-DPAT (0.03 mg kg(-1)). In addition, 20 mg kg(-1) (+/-)pindolol treated animals also had no response to the higher 0.1 mg kg(-1) dose of 8-OH-DPAT. Animals treated for 14 days with a combination of (+/-)pindolol (10 or 20 mg kg(-1)) and fluoxetine were not significantly different from vehicle treated animals when challenged with fluoxetine or 8-OH-DPAT. Taken together it would therefore appear that although (+/-)pindolol alone has sufficient intrinsic activity to produce a de




Exp Eye Res. 2000 May;70(5):551-5.
Effect of fluoxetine on intraocular pressure in the rabbit.

Costagliola C, Mastropasqua L, Capone D, Verolino M, Ciancaglini M, Pisanti N.

Eye Clinic, 2nd University of Naples, Italy.

The effects of fluoxetine, which is a selective inhibitor of serotonin reuptake (SSRI) have been studied on the intraocular pressure (IOP) in the rabbit. IOP was measured using a Perkins tonometer. Intravenous administration of fluoxetine (6.0 mg kg-1) significantly increased IOP by 7.2 +/- 1.3 mmHg (P < 0.001). Fluoxetine administration also reduced the amount of urine excreted during the 24 hr, and increased the urine concentration of 5-hydroxyindole acetic acid (5-HIAA). Topical preadministration of ketanserin prevented a rise in IOP, without there being any effects on the other parameters examined. These findings indicate that intravenous administration of fluoxetine is able to raise IOP, through increased plasma levels of serotonin, which is confirmed by elevated 5-HIAA urine excretion and reduction in diuresis. Ketanserin, a specific 5-HT2A antagonist, counteracts the IOP increase brought about by fluoxetine, thus emphasizing the role of serotonin in the regulation of IOP and stressing the importance of including ophthalmological examination in the protocol of depressed patients undergoing SSRI therapy.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10870512&dopt=Abstract fluoxetine




J Pharmacol Exp Ther. 2000 Jul;294(1):296-301.
Coadministration of 5-hydroxytryptamine(1A) antagonist WAY-100635 prevents fluoxetine-induced desensitization of postsynaptic 5-hydroxytryptamine(1A) receptors in hypothalamus.

Serres F, Muma NA, Raap DK, Garcia F, Battaglia G, Van de Kar LD.

Loyola University of Chicago, Stritch School of Medicine, Department of Pharmacology, Maywood, Illinois 60153, USA.

Treatment with selective serotonin reuptake inhibitors induces a desensitization of hypothalamic postsynaptic 5-hydroxytryptamine (5-HT)(1A) receptors in humans and rats. This study investigated whether fluoxetine-induced desensitization is due to overactivation of postsynaptic 5-HT(1A) receptors; whether blockade of somatodendritic 5-HT(1A) autoreceptors accelerates this desensitization; and whether desensitization is associated with a reduction of Gz proteins, which couple to 5-HT(1A) receptors. WAY-100635 was tested at low doses (0.03-0.3 mg/kg), which antagonize somatodendritic 5-HT(1A) autoreceptors in the raphe nuclei, and at a higher dose (1 mg/kg), which completely blocks postsynaptic 5-HT(1A) receptors. Plasma levels of oxytocin and adrenal corticotrophic hormone (corticotropin) were measured as peripheral indicators of hypothalamic 5-HT(1A) receptor function. Daily injections of fluoxetine (10 mg/kg/day i.p.) for 2 days did not desensitize 5-HT(1A) receptors but three daily injections of fluoxetine produced a partial desensitization of the hormone responses to (+/-)-8-hydroxy-2-dipropylaminoetetralin (50 microg/kg s.c.). WAY-100635 (0.03-0.3 mg/kg) did not accelerate or potentiate the fluoxetine-induced desensitization of 5-HT(1A) receptors. However, WAY-100635 at a dose that completely blocks postsynaptic 5-HT(1A) receptors (1.0 mg/kg) completely prevented the fluoxetine-induced desensitization of 5-HT(1A) receptors. These data demonstrate that at least 3 days of fluoxetine exposure is required to produce a homologous desensitization of hypothalamic 5-HT(1A) receptors. Although previous s

psych.toronto.edu

The results of the present study show that 5 days of systemic treatment with fluoxetine (5 mg/kg) resulted in an augmented locomotor response to amphetamine (0.5 mg/kg). This augmented response to amphetamine was observed 24 and 48 h, but not 5 days, after the cessation of fluoxetine treatment. Subchronic fluoxetine treatment also produced an increase in the brain concentration of amphetamine when rats were challenged with amphetamine 48 h, but not 5 days, after the cessation of fluoxetine treatment. Thus, the effect of subchronic fluoxetine in augmenting amphetamine-induced hyperactivity was consistent with the effect of subchronic fluoxetine in augmenting the amphetamine concentration in the brain. This pattern of results indicates that subchronic fluoxetine potentiates the response to amphetamine within a limited time-window, and that this potentiating effect is likely to be due to the reduced metabolism of amphetamine via the inhibition of cytochrome P450 by fluoxetine and/or its metabolite norfluoxetine.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10877115&dopt=Abstract fluoxetine




Psychopharmacology (Berl). 2000 Mar;148(4):438-42.
The serotonin-1A receptor antagonist WAY-100635 modifies fluoxetine's antidepressant-like profile on the differential reinforcement of low rates 72-s schedule in rats.

Cousins MS, Seiden LS.

Department of Pharmacological and Physiological Sciences, University of Chicago, IL 60637, USA.

RATIONALE: Recent preclinical and clinical data suggest that co-administration of a serotonin-1A (5-HT-1A) receptor antagonist with an antidepressant drug has greater therapeutic efficacy than when the antidepressant drug is administered alone. OBJECTIVE: The purpose of the present experiment was to determine whether pretreatment with the selective 5-HT-1A receptor antagonist N-[2-[4-(2-methoxyphenyl)- 1-piperazinyl]ethyl]-N-(pyridinyl)cyclohexanecarboxamide (WAY-100635; 0.003, 0.03, 0.3 mg/kg, s.c.) would alter the effects of the antidepressant fluoxetine (2.5-10 mg/kg, i.p.) on the differential reinforcement of low-rate 72-s (DRL 72-s) schedule. The DRL 72-s schedule is a behavioral screen selective and sensitive to antidepressant drugs. RESULTS: WAY-100635 had no behavioral effects on its own. The lower doses of fluoxetine (2.5 mg/kg and 5 mg/kg) had no effects, but 10 mg/kg increased reinforcement rate without affecting response rate. The increase in reinforcement rate was blocked by pretreatment with 0.03 mg/kg and 0.3 mg/kg WAY-100635, although the combination of fluoxetine and WAY-100635 also significantly reduced response rate. Interestingly, 0.003 mg/kg or 0.03 mg/kg WAY-100635 administered with 5.0 mg/kg fluoxetine increased reinforcement rate, even though this dose of fluoxetine had no effect on performance. CONCLUSION: These data demonstrate that the behavioral effects of fluoxetine are modified by 5-HT-1A receptor blockade.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10928318&dopt=Abstract fluoxetine




J Neuroendocrinol. 2000 Aug;12(8):736-44.
Regulation of central corticosteroid receptors following short-term activation of serotonin transmission by 5-hydroxy-L-tryptophan or fluoxetine.

Semont A, Fache M, Hery F, Faudon M, Youssouf F, Hery M.

Laboratoire des Interactions fonctionnelles en Neuroendocrinologie, INSERM U501, Universite de la Mediterranee, IFR Jean-Roche, UER de Medecine Nord, Marseille, France.

Alterations of the hypothalamic-pituitary-adrenal (HPA) axis function characterized by a decreased negative feedback capacity are often associated with affective disorders and are corrected by treatment with antidepressant drugs. To gain a better understanding of the effects of the antidepressant drug fluoxetine, a specific serotonin (5-HT) reuptake inhibitor, on central corticosteroid receptors, the effects of short-term activation of serotonin transmission on central corticosteroid receptor expression were analysed in adrenalectomized (ADX) rats either supplemented or not with corticosterone. Serotonin transmission was stimulated either by a single injection of the 5-HT precursor, 5-hydroxy-L-tryptophan (5-HTP), or by a 2-day treatment with fluoxetine. In ADX rats, administration of 5-HTP decreased hippocampal mineralocorticoid (MR) and glucocorticoid (GR) receptor numbers 24 h later, while their respective mRNAs were unchanged and these effects of 5-HTP were mediated by 5-HT2 receptors. In the hypothalamus, GR mRNAs and binding sites decreased 3 h and 24 h after 5-HTP, respectively. By contrast, fluoxetine treatment increased hippocampal MR and GR mRNAs and MR binding sites while GR number remained unchanged. In ADX rats supplemented with corticosterone, 5-HTP and fluoxetine treatment had the same effects on corticosteroid receptors compared to those observed in non supplemented ADX rats: 5-HTP decreased hippocampal MR and GR and hypothalamic GR while fluoxetine treatment increased hippocampal MR. These results show that short-term stimulation of 5-HT transmission by 5-HTP decreases

bms.com

Serotonin 5-HT(1A) receptor antagonists potentiate the effects of serotonin reuptake inhibitors on extracellular serotonin levels in a variety of brain regions. These effects are quite variable, however, with reports indicating potentiations of anywhere from 100-1900%. One factor that might impact the magnitude of such potentiations is the timing of administration of the two agents; reports in which the reuptake inhibitor is given prior to the serotonin receptor antagonist consistently report larger potentiations than reports in which the antagonist is given first. To test this relationship directly, microdialysis and electrophysiology studies were performed to assess the magnitude of increase in extracellular serotonin and changes in cellular activity produced by the serotonin reuptake inhibitor fluoxetine and the 5-HT(1A) receptor antagonist WAY-100635 under various dosing regimens. In microdialysis studies, when WAY-100635 (0.5 mg/kg s.c.) was administered 80 min after fluoxetine (10 mg/kg i.p.) the increase in serotonin was more than twice that observed when the compounds were coadministered. In electrophysiology studies in vivo, WAY-100635 reversed the depression of cell firing produced by fluoxetine when administered 30 min after fluoxetine, but when the two compounds were coadministered, a depression in firing rate was observed comparable to that produced by fluoxetine alone. In contrast, slice recording studies showed that WAY-100635 blocked the effects of fluoxetine regardless of the order of administration. These results indicate that fluoxetine and WAY-100635 can interact in a fashion not predicted by the currently accepted model.