Prozac
Effects of the combination of halothane and serotonin uptake blockers on synaptic transmission in the rat dentate gyrus in vitro.

Frizelle HP, Moriarty DC, O'Connor JJ.

Department of Human Anatomy and Physiology, National University of Ireland, Dublin, Ireland.

Although the exact basis of their action remains unknown, volatile agents affect noradrenergic and serotoninergic systems. Imipramine and fluoxetine have documented effects on these neurotransmitter transmission systems. Given the common sites of action of these antidepressants and halothane, we examined their individual and combined effects on tonic excitatory post-synaptic potentials (EPSPs) and frequency dependent blockade in the rat dentate gyrus in vitro. Extracellular recordings of field EPSPs were maintained from the dentate gyrus, in the presence of picrotoxin (100 microM). Stimulation at 30 Hz (200 ms) allowed investigation of frequency dependent blockade. Once a stable equilibrium was established, halothane, imipramine and fluoxetine were administered via the perfusate and recordings were made. Halothane produced a dose dependent reduction in EPSP amplitude (EC50 0.28 mM; n = 12). Imipramine (1-10 microM) potentiated the EPSP amplitude (148.2 +/- 8.2%; imipramine 1 microM; n = 6). Fluoxetine (0.5-10 microM) reduced EPSP amplitude to 83.7 +/- 22.1% of control (n = 6). In the presence of halothane 0.2 mM, imipramine reduced the EPSP amplitude to 56.5 +/- 9.9% of control (imipramine 10 microM; n = 6; p < 0.05 compared with imipramine alone). Halothane (0.2 mM) demonstrated frequency dependent blockade. However, neither imipramine nor fluoxetine showed use dependent inhibition at the doses investigated. When combined with halothane 0.2 mM, fluoxetine 10 microM demonstrated frequency dependent blockade at the sixth pulse in the train compared with controls (13.8 +/- 4.7% vs 38.1 +/- 8.3%; n = 6; p < 0.05). The halothane-imipramine combination did not exhibit use dependent blockade greater than controls. The reversal of imipramine-induced EPSP potentiation by the preapplication of halothane has not been previously reported. It may be due to modulation of noradrenergic transmission by halothane. The frequency dependent blockade produced by the combination of fluoxetine 10 microM and halothane may be mediated by a nonspecific membrane effect on 5-HT uptake. These differing effects underline the broad action of volatile agents on synaptic mechanisms.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10851661&dopt=Abstract fluoxetine Prozac



Prozac
Serotonin reuptake inhibition does not enhance short term modulation of the exercise ventilatory response.

Henderson DR, Konkle DM, Mitchell GS.

Department of Comparative Biosciences, University of Wisconsin, 2015 Linden Dr. West Madison, WI 53706, USA. hendersd svm.vetmed.wisc.edu

Increased respiratory dead space causes a serotonin (5-HT) dependent augmentation of the exercise ventilatory response known as short term modulation (STM). Contrary to predictions, 5-HT reuptake inhibition with fluoxetine failed to enhance, and even impaired STM with large dead space volumes (0.4-0.6 L). In this study, we tested the hypotheses that: (1) fluoxetine similarly impairs STM with smaller dead space volumes (0.2 L); whereas (2) acute 5-HT release and reuptake inhibition with fenfluramine would enhance STM. Ventilatory and blood gas measurements were made on five goats (37-58 kg) during rest and exercise, with the mask alone or with increased dead space (0.2 L). STM protocols were performed following chronic fluoxetine (>/=21 days, 1 mg/kg, SQ, SID) and acute fenfluramine administration (1 mg/kg, IV). Following fluoxetine, STM was partially impaired. Fenfluramine had no detectable effects on STM. The data suggest that: (1) chronic fluoxetine diminishes STM, possibly via down-regulation of relevant 5-HT receptors, and (2) drugs that release 5-HT acutely do not enhance STM.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10854622&dopt=Abstract fluoxetine Prozac



Prozac
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.

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



Prozac
Effects of chronic fluoxetine treatment in the presence and absence of (+/-)pindolol: a microdialysis study.

Dawson LA, Nguyen HQ, Smith DI, Schechter LE.

Neuroscience Research, Wyeth Ayerst, CN8000, Princeton, New Jersey, 08543-8000, USA. Dawsonl 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 desensitization of the 5-HT(1A) receptor, when given in combination with fluoxetine it is able to prevent the desensitization induced by not only fluoxetine but also itself. This may suggest that the clinical augmentation of antidepressant action by pindolol, when co-administered with a SSRI, is via antagonism of the 5-HT(1A) receptor.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10864885&dopt=Abstract fluoxetine Prozac



Prozac
Fluoxetine decreases concentrations of 3 alpha, 5 alpha-tetrahydrodeoxycorticosterone (THDOC) in major depression.

Strohle A, Pasini A, Romeo E, Hermann B, Spalletta G, di Michele F, Holsboer F, Rupprecht R.

Max Planck Institute of Psychiatry, Kraepelinstrasse 10, 80804, Munich, Germany. stroehle mpipsykl.mpg.de

There is evidence for a differential alteration in the concentrations of 3 alpha-reduced neuroactive steroids in major depression. Because it has been suggested that fluoxetine may shift the activity of the 3 alpha-hydroxysteroid oxidoreductase towards the reductive direction, treatment of major depression may be accompanied by a further increase in plasma 3 alpha, 5 alpha-tetrahydrodeoxycorticosterone (THDOC) concentration. We studied eight male depressed patients before and after treatment with fluoxetine and compared them to healthy age-matched control subjects. Blood samples were quantified for 3 alpha, 5 alpha-tetrahydroprogesterone, 3 alpha,5 beta-tetrahydroprogesterone (THP) and THDOC by means of a highly sensitive combined gas chromatography/mass spectrometry analysis. Compared to control subjects, concentrations of THDOC were higher in depressed patients and decreased after fluoxetine treatment. In contrast, THP concentrations were lower in depressed patients and increased after fluoxetine treatment. Our results give further evidence for a disequilibrium of 3 alpha-reduced neuroactive steroids in major depression, which is normalized by treatment with fluoxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10867112&dopt=Abstract fluoxetine Prozac



Prozac
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.

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



Prozac
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 studies indicate that injections of fluoxetine for 14 days produce a reduction of Gz protein levels in the hypothalamus, the levels of Gz proteins were not affected by either fluoxetine or WAY-100635. Alternative mechanisms mediating the initial stages of 5-HT(1A) receptor desensitization could involve post-translational modifications in the 5-HT(1A) receptor-Gz protein-signaling cascade.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10871325&dopt=Abstract fluoxetine Prozac



Prozac
Subchronic fluoxetine administration to rats: effects on 5-HT autoreceptor activity as measured by in vivo microdialysis.

Dremencov E, Gur E, Lerer B, Newman ME.

Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah-Hebrew University Medical Center, P.O.B. 12000, 91120, Jerusalem, Israel.

Subchronic administration of fluoxetine to rats has been shown to induce subsensitivity of presynaptic 5-HT(1A) and 5-HT(1B) autoreceptors, and also postsynaptic 5-HT(1A) receptors in the hypothalamus. We investigated the effects of administration of fluoxetine (10 mg/kg i.p.) to rats for 6 days on presynaptic 5-HT(1A) receptor activity in the hypothalamus, postsynaptic 5-HT(1A) receptor activity in the hippocampus, and presynaptic 5-HT(1B) autoreceptor activity in both areas, using in vivo microdialysis. The effect of the 5-HT(1B/1D) antagonist (N-[4-methoxy-3-(4-methyl-1-piperizinyl)phenyl]-2'-methyl-4'-(5- methyl-1,2,4-oxadiazole-3-yl)[1,1'-biphenyl]-carboxamide (GR 127935) (5 mg/kg s.c.) to elevate 5-hydroxytryptamine (5-HT) levels was reduced in hippocampus but not hypothalamus of fluoxetine-treated rats. Fluoxetine did not alter either presynaptic 5-HT(1A) autoreceptor activity, as measured by the effect of injection of 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) (0.2 mg/kg or 50 microg/kg s.c.) on 5-HT levels in the hypothalamus, or postsynaptic 5-HT(1A) receptor activity, as measured by the effect of 8-OH-DPAT (0.2 mg/kg s.c.) on cyclic AMP accumulation, in the hippocampus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10871704&dopt=Abstract fluoxetine Prozac