Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12599-604.
Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography.

Uzunov DP, Cooper TB, Costa E, Guidotti A.

Department of Psychiatry, University of Illinois at Chicago 60612, USA.

Fluoxetine administered intraperitoneally to sham-operated or adrenalectomized/castrated (ADX/CX) male rats dose-dependently (2.9-58 mumol/kg i.p.) increased the brain content of the neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone, 3 alpha, 5 alpha-TH PROG). The increase of brain 3 alpha, 5 alpha-TH PROG content elicited by 58 mumol/kg fluoxetine lasted more than 2 hr and the range of its extent was comparable in sham-operated (approximately 3-10 pmol/g) and ADX/CX rats (2-9 pmol/g) and was associated with a decrease (from 2.8 to 1.1 pmol/g) in the 5 alpha-pregnan-3,20-dione (5 alpha-dihydroprogesterone, 5 alpha-DH PROG) content. The pregnenolone, progesterone, and dehydroepiandrosterone content failed to change in rats receiving fluoxetine. The extent of 3 alpha, 5 alpha-TH PROG accumulation elicited by fluoxetine treatment differed in various brain regions, with the highest increase occurring in the olfactory bulb. Importantly, fluoxetine failed to change the 3 alpha, 5 alpha-TH PROG levels in plasma, which in ADX/CX rats were at least two orders of magnitude lower than in the brain. Two other serotonin re-uptake inhibitors, paroxetine and imipramine, in doses equipotent to those of fluoxetine in inhibiting brain serotonin uptake, were either significantly less potent than fluoxetine (paroxetine) or failed to increase (imipramine) 3 alpha, 5 alpha-TH PROG brain content. The addition of 10 microM of 5 alpha-DH PROG to brain slices of ADX/CX rats preincubated with fluoxetine (10 microM, 15 min) elicited an accumulation of 3 alpha, 5 alpha-TH PROG greater than in slices preincubated with vehicle. A fluoxetine stimulation of brain 3 alpha, 5 alpha-TH PROG biosynthesis might be operative in the anxiolytic and antidys




Neuropsychopharmacology. 1996 Nov;15(5):515-22.
Chronic fluoxetine reduces serotonin transporter mRNA and 5-HT1B mRNA in a sequential manner in the rat dorsal raphe nucleus.

Neumaier JF, Root DC, Hamblin MW.

Department of Psychiatry, University of Washington, USA.

In major depression in humans and in animal models of depression, there is a defect in serotonergic neurotransmission that can be relieved by chronic antidepressant treatment. One possibility is that this pathologic state is caused by excessive presynaptic autoreceptor activity in serotonergic neurons, and that antidepressants down-regulate the number of these inhibitory receptors, allowing more normal serotonin release to occur. To evaluate this hypothesis, we measured the effects of the antidepressant fluoxetine on neuronal levels of 5-HT1B receptor mRNA, the putative serotonin terminal autoreceptor in rat brain, and on serotonin transporter mRNA, the direct site of fluoxetine binding. Fluoxetine reduced serotonin transporter mRNA briefly, but this was not sustained after 21 days of treatment. However, fluoxetine reduced dorsal raphe 5-HT1B mRNA levels in a time-dependent and washout-reversible manner. This reduction in 5-HT1B mRNA was specific to dorsal raphe nucleus and was not found in several postsynaptic (nonserotonergic) regions. These results suggest that chronic fluoxetine may increase serotonin release from axonal terminals by down-regulating the messenger RNA coding for presynaptic 5-HT1B autoreceptors while causing only transient effects on serotonin transporter mRNA.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8914125&dopt=Abstract fluoxetine




J Clin Pharmacol. 1996 Jan;36(1):42-7.
Excretion of fluoxetine and its metabolite, norfluoxetine, in human breast milk.

Taddio A, Ito S, Koren G.

Faculty of Medicine, University of Toronto, Canada.

A study was conducted to measure breast milk concentrations of fluoxetine and its active metabolite, norfluoxetine, excreted in breast milk in a cohort of nursing women using fluoxetine, and to estimate infant dose from nursing. The study included 10 women nursing 11 infants (median age, 185 days). The mean fluoxetine dose was 0.39 mg/kg/day. Each patient manually collected 3 to 6 milk samples throughout a dosing interval. Concentrations of fluoxetine and norfluoxetine in milk were measured by gas-liquid chromatography. Mothers reported whether they observed adverse effects in their infants. The average infant doses of fluoxetine and norfluoxetine, as estimated for an exclusively breast-fed infant ingesting 1000 mL of milk per day, were 0.077 mg (SD = 0.054 mg) and 0.084 mg (SD = 0.043 mg), respectively. The total dose of fluoxetine and norfluoxetine (expressed as fluoxetine equivalents) was 0.165 mg (SD = 0.092 mg), which was equivalent to 10.8% (SD = 2.2%) of the maternal dose, adjusted on a mg/kg basis in a 4-kg infant. No adverse events were reported by mothers in their infants. Approximately one tenth of the adult therapeutic dose of fluoxetine is excreted in breast milk. Although short-term adverse effects in the infant from exposure through nursing were not reported in this cohort, future studies that assess the potential long-term consequences are needed.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8932542&dopt=Abstract fluoxetine




Clin Pharmacol Ther. 1996 Nov;60(5):512-21.
The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin.

Hamelin BA, Turgeon J, Vallee F, Belanger PM, Paquet F, LeBel M.

School of Pharmacy, Universite Laval, Quebec Heart Institute, Laval Hospital, Sainte-Foy, Canada.

BACKGROUND: Substrates and inhibitors of the cytochrome P450 isozyme CYP2D6 have overlapping structural characteristics. Two prototype serotonin uptake inhibitors, sertraline and fluoxetine, share these structural criteria and have been identified as potent inhibitors of CYP2D6 in vitro. The current study was undertaken to investigate whether genetically determined CYP2D6 activity alters the disposition of sertraline or fluoxetine or both. METHODS: Single doses of sertraline (50 mg) and fluoxetine (20 mg) were administered successively to 20 young men with high (extensive metabolizers; n = 10) and low (poor metabolizers; n = 10) CYP2D6 activity. Blood and urine samples were collected for 5 to 7 half-lives and sertraline, desmethylsertraline, fluoxetine, and norfluoxetine were determined by GC and HPLC techniques. RESULTS: Poor metabolizers had significantly greater fluoxetine peak plasma concentrations (Cmax; increases 57%), area under the concentration versus time curve (AUCzero-->infinity; increases 290%), and terminal elimination half-life (increases 216%) compared with extensive metabolizers. The total amount of fluoxetine excreted in the urine during 8 days was almost three times higher in poor metabolizers than in extensive metabolizers (719 versus 225 micrograms; p < 0.05), whereas the total amount of norfluoxetine excreted in urine of poor metabolizers was about half of that of extensive metabolizers (524 versus 1047 micrograms; p < 0.05). Norfluoxetine Cmax and AUCzero-->t were significantly smaller in poor metabolizers (decreases 55% and decreases 53%, respectively), and the partial metabolic clearance of fluoxetine into norfluoxetine was 10 times smaller in this group (4.3




J Neural Transm. 1996;103(1-2):131-46.
The synergistic effect of fluoxetine on the locomotor hyperactivity induced by MK-801, a non-competitive NMDA receptor antagonist.

Maj J, Rogoz Z, Skuza G, Wedzony K.

Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.

It was found previously that the MK-801 (an uncompetitive NMDA receptor antagonist)-induced locomotor hyperactivity in rats was potently increased by antidepressant drugs. The present paper analysed the locomotor hyperactivity induced by combined treatment with fluoxetine + MK-801 in male Wistar rats. The MK-801 hyperactivity was increased by citalopram (the latter effect was prevented by zacopride and ketanserin), sertraline, p-chloramphetamine, 8-OH-DPAT and TFMPP. The hyperlocomotion caused by fluoxetine + MK-801 was antagonized by tropisetron and zacopride and, to a lesser extent, by ketanserin, ritanserin and NAN-190, but not by WAY 100135, pindolol, metergoline or mianserin. Sulpiride and clozapine were able to inhibit the fluoxetine + MK-801 hyperlocomotion. The hyperlocomotion induced by D-amphetamine or apomorphine was not modified by fluoxetine or citalopram. Fluoxetine increased the release of dopamine (measured by a microdialysis method) in the striatum, induced by MK-801. The obtained results indicate that fluoxetine increases the MK-801-induced locomotor hyperactivity via activation of 5-HT3 receptors and, to a lesser degree, 5-HT2 ones.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9026367&dopt=Abstract fluoxetine




Br J Pharmacol. 1995 Sep;116(2):1923-31.
Differential effects of acute and chronic fluoxetine administration on the spontaneous activity of dopaminergic neurones in the ventral tegmental area.

Prisco S, Esposito E.

Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud, Chieti, Italy.

1. Electrophysiological techniques were used to study the effects of fluoxetine and citalopram on the basal activity of dopaminergic neurones in the ventral tegmental area (VTA) and substantia nigra, pars compacta (SNc) of rats. 2. Acute i.v. injection of fluoxetine (20-1280 micrograms kg-1) caused a dose-dependent inhibition of the firing rate of VTA dopaminergic neurones, but did not affect the activity of dopaminergic cells in the SNc. Citalopram (20-1280 micrograms kg-1, i.v.) inhibited the firing rate of dopaminergic neurones in the VTA, but its effect (maximal inhibition: 14 +/- 7%) was less pronounced than that of fluoxetine (maximal inhibition: 34 +/- 7%). 3. Pretreatment with mesulergine (80 micrograms kg-1, i.v.), a 5-hydroxytryptamine2C/2B (5-HT2C/2B) receptor antagonist, blocked the inhibitory effect of fluoxetine on VTA dopaminergic cells. Selective lesions of 5-hydroxytryptaminergic neurones by the neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), abolished the fluoxetine-induced reduction of VTA dopaminergic activity. 4. In a series of experiments, fluoxetine (10 mg kg-1, i.p.) was administered once daily for 21 consecutive days. Acute i.v. administration of fluoxetine (20-1280 micrograms kg-1, 72 h after the last i.p. injection) did not cause any change in the basal firing rate of VTA dopaminergic neurones in treated rats, whereas it induced the typical inhibitory effect in control animals. A group of rats chronically treated with fluoxetine, received i.v. m-chlorophenylpiperazine (mCPP; 10-320 micrograms kg-1), a 5-HT2C/2B receptor agonist. This drug significantly inhibited VTA dopaminergic function in control rats, but did not modify the basal activity of dopaminergic cells in




J Pharmacol Exp Ther. 1995 Dec;275(3):1131-5.
Effect of fluoxetine, norfluoxetine, sertraline and desmethyl sertraline on human CYP3A catalyzed 1'-hydroxy midazolam formation in vitro.

Ring BJ, Binkley SN, Roskos L, Wrighton SA.

Department of Drug Metabolism and Disposition, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, USA.

The ability of fluoxetine, norfluoxetine, sertraline and desmethyl sertraline to inhibit the CYP3A subfamily of cytochromes P450 was examined in vitro, using the formation of 1'-hydroxy midazolam as a probe for CYP3A catalytic activity. The inhibition observed with these four compounds was modeled using competitive, noncompetitive, uncompetitive and mixed competitive/noncompetitive relationships by nonlinear regression analysis. The best fit model of the inhibition of CYP3A-mediated 1'-hydroxy midazolam formation by all four compounds examined was determined to be mixed inhibition. The calculated Ki values were 65.7 +/- 12.0 microM for fluoxetine, 19.1 +/- 1.9 microM for norfluoxetine, 64.4 +/- 11.6 microM for sertraline and 48.1 +/- 11.6 microM for desmethyl sertraline. Steady-state plasma levels of fluoxetine and norfluoxetine can approach a concentration of 1 microM (approximately 350 ng/ml of plasma). Assuming an inhibitor concentration of 1 microM and a concentration of the substrate substantially below its Km (at least 10-fold lower), the results reported predict that fluoxetine and norfluoxetine together would inhibit CYP3A catalytic activity by less than 7% (less than 0.7% if the unbound plasma concentration of fluoxetine is considered). By using the same assumptions and concentrations for sertraline and desmethyl sertraline, these agents together would be predicted to inhibit the metabolic clearance of a coadministered CYP3A metabolized drug by less than 4%. The observations reported here suggest that fluoxetine and sertraline would have little effect on CYP3A-mediated clearance of coadministered drugs.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8531073&dopt=Abstract fluoxetine




Neurosci Lett. 1994 May 23;173(1-2):210-2.
Inhibition of a 5-HT3 receptor-mediated current by the selective serotonin uptake inhibitor, fluoxetine.

Fan P.

Laboratory of Molecular and Cellular Neurobiology, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD 20852.

The effect of the selective serotonin uptake inhibitor, fluoxetine, on the inward current mediated by 5-HT3 receptors was investigated with the whole-cell patch-clamp technique. Fluoxetine inhibited the peak 5-HT current with an IC50 value of 1.2 microM. During continuous application of fluoxetine at concentrations of < or = 1 microM, there was a transient decrease in the fluoxetine-induced inhibition of 5-HT current. It is suggested that fluoxetine may have a short-lived action on 5-HT current and that the 5-HT3 receptor is a possible acting site for the therapeutic use of fluoxetine.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7523998&dopt=Abstract fluoxetine




Am J Psychiatry. 1995 Jan;152(1):122-5.
Fluoxetine and extrapyramidal side effects.

Coulter DM, Pillans PI.

University of Otago Medical School, Dunedin, New Zealand.

OBJECTIVE: The authors' goal was to determine whether fluoxetine is associated with extrapyramidal side effects. METHOD: They assessed the notifications of extrapyramidal manifestations in patients given fluoxetine in the New Zealand Intensive Medicines Monitoring Programme, a national system that monitored adverse reactions associated with fluoxetine over a 4-year period, and determined whether these adverse reactions were causally related to fluoxetine. RESULTS: In reports of adverse reactions in 5,555 patients given fluoxetine throughout New Zealand, there were 15 notifications of extrapyramidal events probably or possibly caused by fluoxetine. Fluoxetine was the only psychotropic agent used for seven of the 15 patients; two patients were also taking lithium, four were taking neuroleptics, two were taking tricyclic antidepressants, and one was taking metoclopramide. CONCLUSIONS: The authors conclude that fluoxetine may be associated with extrapyramidal reactions. These may occur with fluoxetine alone or fluoxetine may facilitate the reaction in patients receiving psychotropic medication or dopamine receptor blocking drugs.

Source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7802102&dopt=Abstract fluoxetine