J Neurochem. 1997 Mar;68(3):1159-63.
Potentiation of the fluoxetine-induced increase in dialysate levels of serotonin (5-HT) in the frontal cortex of freely moving rats by combined blockade of 5-HT1A and 5-HT1B receptors with WAY 100,635 and GR 127,935.

Gobert A, Rivet JM, Cistarelli L, Millan MJ.

Psychopharmacology Department, Centre de Recherches de Croissy, Croissy-sur-Seine, France.

In this study, we examined the influence of blockade of serotonin (5-HT)1A and/or 5-HT1B autoreceptors on the fluoxetine-induced increase in dialysate levels of 5-HT as compared with dopamine (DA) and noradrenaline (NAD) in single samples of the frontal cortex (FCx) of freely moving rats. Fluoxetine (10.0 mg/kg, s.c.) elicited a twofold increase in dialysate levels of 5-HT relative to baseline values. The selective 5-HT1A antagonist WAY 100,635 (0.16 mg/kg, s.c.) did not influence 5-HT release alone but doubled the influence of fluoxetine on basal levels. Similarly, the selective 5-HT 1B/1D antagonist GR 127,935 (2.5 mg/kg, s.c.) did not alter basal 5-HT levels alone and doubled the fluoxetine-induced increase in 5-HT levels. Combined administration of WAY 100,635 and GR 127,935 elicited an (at least) additive rise in the fluoxetine-induced increase in 5-HT levels to eightfold basal values, without modifying resting 5-HT levels. These changes were selective for 5-HT inasmuch as the parallel (twofold) increase in DA and NAD levels provoked by fluoxetine was not potentiated. The present data demonstrate that combined blockade of 5-HT1A and 5-HT1B autoreceptors markedly and selectively potentiates the fluoxetine-induced increase in dialysate levels of 5-HT versus DA and NAD in the FCx of freely moving rats. These observations suggest that 5-HT 1A/1B antagonism may represent a novel strategy for the improvement in the therapeutic profile of 5-HT reuptake inhibitor antidepressant agents and that 5-HT may be primarily involved in such interactions.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9048762&dopt=Abstract fluoxetine




J Neurochem. 1997 Mar;68(3):1326-9.
Buspirone enhances duloxetine- and fluoxetine-induced increases in dialysate levels of dopamine and noradrenaline, but not serotonin, in the frontal cortex of freely moving rats.

Gobert A, Rivet JM, Cistarelli JM, Millan MJ.

Psychopharmacology Department, Centre de Recherches de Croissy Croissy-sur-Seine, France.

A serotonin (5-HT)1A receptor partial agonist, buspirone, potentiates the clinical antidepressant properties of 5-HT reuptake inhibitors (SSRIs). Herein, we examined the interaction of buspirone with two SSRIs, duloxetine and fluoxetine, on extracellular levels of 5-HT, dopamine (DA), and noradrenaline (NAD) in single dialysate samples of freely moving rats. Duloxetine (5.0 mg/kg. s.c.) and fluoxetine (10.0 mg/kg, s.c.) increased dialysate levels of DA (65 and 60% vs. basal values, respectively). NAD (400 and 90%, respectively), and 5-HT (130 and 110%, respectively) in the frontal cortex (FCX). Buspirone (2.5 mg/kg, s.c.) similarly elevated levels of DA (100%) and NAD (160%) but reduced those of 5-HT (-50%). Administered with buspirone, the ability of duloxetine and fluoxetine to increase 5-HT levels was transiently inhibited (over 60 min), although by the end of sampling (180 min) their actions were fully expressed. In contrast, buspirone markedly and synergistically facilitated the elevation in DA levels elicited by duloxetine (550%) and fluoxetine (240%). Furthermore, buspirone potentiated the induction of NAD levels by duloxetine (750%) and fluoxetine (350%). These data suggest that a reinforcement in the influence of SSRIs on DA and possibly. NAD but not 5-HT release in FCX may contribute to their increased antidepressant activity in the presence of buspirone. More generally, they support the hypothesis that a reinforcement in dopaminergic transmission in the FCX contributes to the actions of SSRIs and other antidepressant drugs.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9048781&dopt=Abstract fluoxetine




Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):2036-40.
Blockage of 5HT2C serotonin receptors by fluoxetine (Prozac).

Ni YG, Miledi R.

Department of Psychobiology, University of California, Irvine 92697-4550, USA.

Fluoxetine (Prozac) inhibited the membrane currents elicited by serotonin (5-hydroxytryptamine; 5HT) in Xenopus oocytes expressing either cloned 5HT2C receptors or 5HT receptors encoded by rat cortex mRNA. Responses of 5HT2C receptors, elicited by nM concentrations of 5HT, were rapidly and reversibly blocked by micromolar concentrations of fluoxetine. For responses elicited by 1 microM 5HT, the IC50 of fluoxetine inhibition was approximately 20 microM. In accord with the electrophysiological results, fluoxetine inhibited the binding of [3H]5HT to 5HT2C receptors expressed in HeLa cells (Ki approximately 65-97 nM), and the binding to 5HT receptors in rat cortex membranes was also inhibited but less efficiently (Ki approximately 56 microM). Our results show that fluoxetine is a competitive and reversible antagonist of 5HT2C receptors and suggest that some therapeutic effects of fluoxetine may involve blockage of 5HT receptors, in addition to its known blockage of 5HT transporters. Similar work may help to design more selective compounds for use in the treatment of brain disorders.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9050900&dopt=Abstract fluoxetine

ghc.org

While fluoxetine is considerably more expensive than tricyclic antidepressants (TCAs), some previous studies have suggested that general medical expenditures are lower among patients treated with fluoxetine. In this study, computerised pharmacy and cost-accounting records of a large health plan were used to examine overall treatment costs for 5169 primary-care patients beginning antidepressant treatment with fluoxetine or one of 2 TCAs, imipramine or desipramine. Comparison was based on initial medication prescribed, regardless of subsequent switches or discontinuation. Patients treated with fluoxetine were older, with a higher burden of medical illness and higher overall health-service costs before starting antidepressant treatment, compared with patients receiving the other 2 drugs. Initial choice of fluoxetine was associated with approximately $US140 higher mean antidepressant costs and approximately $US300 higher mean costs for all other health services (1995 costs). Alternative methods of accounting for baseline differences (age, medical comorbidity, prior costs) indicated that adjusted 'non-antidepressant' costs (total costs minus costs of antidepressant therapy) in the fluoxetine group were $US75 to $US300 lower than in either of the TCA groups, but these differences were not statistically significant. Subgroup analyses suggested that the use of fluoxetine was associated with lower overall costs only among those incurring high costs in the pretreatment period. These findings support earlier studies suggesting that the use of fluoxetine as a first-line antidepressant in primary care will increase antidepressant drug costs, but will not significantly increase total treatment costs.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10175986&dopt=Abstract fluoxetine




Pharmacol Biochem Behav. 1995 Oct;52(2):341-6.
Effect of fluoxetine on learning and memory involves multiple 5-HT systems.

Meneses A, Hong E.

Terapeutica Experimental Depto. de Farmacologia y Toxicologia, CINVESTAV-IPN, Tepepan, Mexico, Mexico.

Diverse evidence suggests that 5-HT uptake blockers enhance learning and memory. However, there is no information about the mechanisms of action involved in such effects. The aim of the present work was to investigate the nature of the receptors involved in the effects of fluoxetine on learning. Therefore, a dose-response curve of posttraining injection (intraperitoneal) of fluoxetine was carried out in an associative learning task (auto-shaping). Fluoxetine or the vehicle was injected 10 min after 5-HT antagonists: (+/-)-pindolol, (+/-)-propanolol, NAN-190, ketanserin, ritanserin, mesulergine, MDL 72222, or SDZ 205-557. Presynaptic activity was eliminated by means of chloroamphetamine pretreatment. Scopolamine (an anticholinergic) and dizocilpine (a noncompetitive NMDA receptor antagonist) were also used. Results showed that fluoxetine enhanced learning of the conditioned response (CR) in a dose-dependent fashion. All 5-HT antagonists had no effects by themselves but inhibited the effects of fluoxetine at different degrees. Decrement of CR produced by scopolamine was reversed by fluoxetine. Dizocilpine did not affect CR but prevented the effects of fluoxetine. The present findings suggest that the actions of fluoxetine on learning are due to an interaction with multiple receptors of postsynaptic nature.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8577800&dopt=Abstract fluoxetine




Gastroenterology. 1996 May;110(5):1438-45.
Modulation of ionic currents in isolated canine and human jejunal circular smooth muscle cells by fluoxetine.

Farrugia G.

Division of Gastroenterology and Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.

BACKGROUND & AIMS: Fluoxetine is a commonly prescribed antidepressant with frequent gastrointestinal side effects. The aim of this study was to examine the effects of fluoxetine on isolated canine and human jejunal circular smooth muscle cells. METHODS: Patch clamp and dual wavelength ratio techniques were used. RESULTS: In amphotericin-perforated patch whole-cell recordings, fluoxetine at 100 nmol/L, 1 mumol/L, and 10 mumol/L concentrations decreased the outwardly delayed rectifier potassium current in canine cells by 12% +/- 3%, 27% +/- 12%, and 37% +/- 3%, respectively, and depolarized the membrane potential by 9.7 +/- 1.8 mV at 10 mumol/L. At 100 mumol/L and 1 mmol/L concentrations, fluoxetine increased the outward current by 88% +/- 40% and 475% +/- 270%, respectively. The increase in the outward current was blocked by charybdotoxin, suggesting an effect on the calcium-activated potassium current. In human cells, fluoxetine at 1 mumol/L decreased the outward potassium current by 26% +/- 4% and at 100 mumol/L increased the outward potassium current by 134% +/- 22%. CONCLUSIONS: Fluoxetine had direct effects on canine and human jejunal circular smooth muscle cells. Low concentrations decreased the outwardly delayed rectifier potassium current, and higher concentrations activated calcium-activated potassium channels. The results may in part explain the frequent gastrointestinal side effects of the drug.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8613049&dopt=Abstract fluoxetine




Gen Hosp Psychiatry. 1996 Jan;18(1):8-13.
Fluoxetine in depressed patients with renal failure and in depressed patients with normal kidney function.

Levy NB, Blumenfield M, Beasley CM Jr, Dubey AK, Solomon RJ, Todd R, Goodman A, Bergstrom RR.

Department of Psychiatry and Medicine, Westchester County Medical Center, Valhalla, NY, USA.

Nine depressed patients with normal kidney function and seven depressed patients with renal failure undergoing hemodialysis were treated with open-label fluoxetine 20 mg/day in an 8-week study. The study was designed to evaluate the pharmacokinetics of fluoxetine during repeated administration and to acquire preliminary data regarding the effectiveness of this antidepressant in a population undergoing hemodialysis. Six patients in each group completed the study. Of these, five patients undergoing hemodialysis and five patients with normal renal function experienced moderate to marked improvement in their depression. Side effects were equal and minor in both groups, indicating that fluoxetine is safe in patients with renal impairment. The mean +/- standard deviation steady-state plasma concentrations of the sum of fluoxetine plus its metabolite norfluoxetine for patients completing 8 weeks (N = 6, both groups) were comparable for the patients undergoing hemodialysis (253 +/- 61 ng/ml) and those with normal kidney function (218 +/- 122 ng/ml; t = 1.5, df = 70, p > 0.13). These data suggest that the efficacy of fluoxetine in patients with renal failure undergoing hemodialysis is comparable to that in patients with normal kidney function. These data further suggest that renal failure and the process of hemodialysis do not materially alter the pharmacokinetics of fluoxetine or its major metabolite norfluoxetine.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8666216&dopt=Abstract fluoxetine




Br J Clin Pharmacol. 1995 Nov;40(5):481-5.
The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4'-hydroxylase activity in human liver microsomes.

Kobayashi K, Yamamoto T, Chiba K, Tani M, Ishizaki T, Kuroiwa Y.

Department of Clinical Pharmacy, Showa University, Tokyo, Japan.

The inhibitory effects of four selective serotonin reuptake inhibitors (SSRIs), fluoxetine, sertraline, paroxetine and citalopram, and three metabolites (norfluoxetine, demethylcitalopram and didemethylcitalopram), on S-mephenytoin 4'-hydroxylation activities in human liver microsomes were studied. The 4'-hydroxylation of S-mephenytoin, a representative substrate toward CYP2C19, was competitively inhibited by all the SSRIs and their metabolites studied. The mean Ki values of fluoxetine, norfluoxetine, sertraline, paroxetine, citalopram, demethylcitalopram and didemethylcitalopram were 5.2, 1.1, 2.0, 7.5, 87.3, 55.8 and 7.7 microM, respectively. The findings suggest that some SSRIs and their metabolites with a low Ki value (e.g., fluoxetine, norfluoxetine) may reduce the clearance of drugs metabolized by this isoform of P450, thereby resulting in a possible drug-drug interaction, when administered simultaneously. In addition, SSRIs and their metabolites examined herein may be substrates toward CYP2C19.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8703653&dopt=Abstract fluoxetine




Neurotoxicol Teratol. 1996 May-Jun;18(3):289-96.
Modification of acoustic startle reactivity by cocaine administration during the postnatal period: comparison with a specific serotonin reuptake inhibitor.

Dow-Edwards DL.

Department of Pharmacology, State University of New York Health Science Center, Brooklyn 11203, USA.

This study investigated whether exposure to cocaine during postnatal period affects the acoustic startle response (ASR) following administration of the serotonin (5-HT) agonists, 8-OH-DPAT and mCPP, in adulthood. To test the hypothesis that alterations in reactivity may be due to cocaine's effects at the 5-HT carrier, another group of rats was given fluoxetine, a specific 5-HT uptake inhibitor, during the same postnatal period and tested along with the cocaine-treated rats. Male and female rats received 25 mg/kg/day cocaine HCl, fluoxetine HCl, or vehicle SC during postnatal days 11-20. At 75 days of age, subjects were ASR tested for 30 min on 2 consecutive days. On the first test day, there was a significant effect of treatment and gender with post hoc analysis indicating that, overall, the males were more reactive than the females and that the fluoxetine-treated males showed a pattern of reactivity resembling sensitization. On the second test day, subjects received a dose of the 5-HT1A agonist 8-OH-DPAT, the 5-HT1B/2C agonist, mCPP, or saline prior to being placed in the startle chamber. Cocaine-exposed males showed an enhanced response to 8-OH-DPAT and a reduction in the depression produced by mCPP administration compared to their response to saline. Fluoxetine exposed males showed a significant increase in startle response following saline administration compared to the rats receiving vehicle during the postnatal period and 8-OH-DPAT produced an insignificant enhancement of that startle response. mCPP reduced startle in fluoxetine-treated males as it did in the postnatal vehicle-treated controls. In females, the postnatal cocaine and fluoxetine treatments did not alter the respon