Prozac
Fluoxetine-induced desensitization of somatodendritic 5-HT1A autoreceptors is independent of glucocorticoid(s).

Le Poul E, Laaris N, Hamon M, Lanfumey L.

NeuroPsychoPharmacologie, INSERM U.288, CHU Pitie-Salpetriere, Paris, France.

Previous in vitro studies showed that glucocorticoid receptor activation (notably by corticosterone) could induce a functional desensitization of somatodendritic 5-HT1A autoreceptors in the dorsal raphe nucleus [Laaris et al. (1995) Neuropharmacology 34:1201-1210], similar to that due to in vivo subchronic treatment with a 5-HT reuptake inhibitor, such as fluoxetine, in rats. In the present study, we investigated whether a link might exist between these effects, i.e., whether glucocorticoid receptor activation could be responsible for the fluoxetine-induced desensitization of 5-HT1A autoreceptors. In vitro recording in the dorsal raphe nucleus of brain-stem slices showed that subchronic treatment with fluoxetine (5 mg/kg intraperitoneally (i.p.), daily for 3-7 days) significantly reduced the potency of the 5-HT1A receptor agonist ipsapirone to inhibit the firing rate of serotoninergic neurons. Parallel experiments in adrenalectomized and sham-operated rats indicated that subchronic fluoxetine treatment produced a similar shift to the right of the ipsapirone inhibition curve in both groups of animals. Furthermore, the subchronic blockade of glucocorticoid receptors by RU 38486 (25 mg/kg subcutaneously (s.c.), daily) in intact rats treated with fluoxetine (5 mg/kg i.p., daily for 3 days) did not affect the ability of the latter treatment to reduce the potency of ipsapirone to inhibit the firing of serotoninergic neurons. These data suggest that glucocorticoid receptors (and their possible activation by corticosterone) are not involved in the functional desensitization of somatodendritic 5-HT1A autoreceptors, which occurs during long-term treatment with a serotonin reuptake inhibitor such as fluoxetine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9372553&dopt=Abstract fluoxetine Prozac



Prozac
Autoradiographic evidence for differential G-protein coupling of 5-HT1A receptors in rat brain: lack of effect of repeated injections of fluoxetine.

Li Q, Battaglia G, Van de Kar LD.

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

The present study examined the distribution of [3H]8-OH-DPAT-labeled 5-HT1A receptors and their degree of coupling to G proteins in the hypothalamus and several other brain regions. In addition, we also investigated the effects of repeated injections of fluoxetine on the density and G protein coupling of 5-HT1A receptors in hypothalamic nuclei and other brain regions using autoradiography. Male rats received daily injections of either fluoxetine (10 mg/kg, ip) for 3, 7, 14 and 22 days, or saline for 22 days. 5-HT1A receptors were labeled by 2 nM [3H]8-hydroxy-2-(dipropylamino)tetralin ([3H]8-OH-DPAT) in the absence or presence of guanylylimidodiphosphate (Gpp(NH)p, 10[-5] M) to determine the percentage of 5-HT1A receptors coupled to G proteins. 5-HT1A receptor densities ranged from 7 to 63 fmol/mg tissue equivalent among hypothalamic nuclei. Similarly, the degree of G protein coupling to 5-HT1A receptors varied markedly among hypothalamic nuclei (from 14% to 61%) and among other brain regions (from 17% to 85%). Fluoxetine did not alter the density or the degree of coupling of 5-HT1A receptors in any brain regions. These data indicate marked regional differences in the degree of G protein-coupled 5-HT1A receptors and suggest that fluoxetine-induced desensitization of hypothalamic 5-HT1A receptors is not mediated by changes in receptor density or G protein coupling.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9374282&dopt=Abstract fluoxetine Prozac



Prozac
Prescribing of selective serotonin reuptake inhibitors, anxiolytics, and sedative-hypnotics by general practitioners in The Netherlands: a multivariate analysis.

Pathiyal A, Hylan TR, Jones JK, Davtian D, Sverdlov L, Keyser M.

Degge Group, Ltd., Arlington, Virginia, USA.

A study of the prescribing of anxiolytics and sedative-hypnotics and the occurrence of anxiety or sleep disorders before and after the initiation of selective serotonin reuptake inhibitor (SSRI) therapy may provide insight into differences in individual SSRIs. The purpose of our study was to evaluate whether and in what way the likelihood of being prescribed an anxiolytic or sedative-hypnotic or receiving a diagnosis of an anxiety or sleep disorder differed in patients prescribed either fluoxetine or paroxetine by a general practitioner (GP) in the Netherlands, where these two agents are the most commonly prescribed SSRIs. Episodes of SSRI treatment were constructed from a recently available GP database in the Netherlands. Logistic regression analysis was used to determine whether, after controlling for other observable factors, the receipt of paroxetine or fluoxetine was a statistically significant determinant for receipt of an anxiolytic or sedative-hypnotic or a diagnosis of an anxiety or sleep disorder. We found that patients who were prescribed fluoxetine as their index drug were less likely to receive a concomitant sedative-hypnotic on their index date compared with patients receiving paroxetine. After controlling for other observable factors, such as use of anxiolytics and sedative-hypnotics before SSRI therapy or on the index date or the existence of comorbid anxiety or sleep disorders, patients starting fluoxetine therapy were no more likely than patients starting paroxetine therapy to receive an anxiolytic or sedative-hypnotic or a diagnosis of an anxiety or sleep disorder during the 60-day post period. The likelihood of a patient's being diagnosed with or receiving a prescription for an anxiety or sleep disorder does not appear to be a differentiating factor between the prescribing of fluoxetine or paroxetine by GPs in the Netherlands.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9377622&dopt=Abstract fluoxetine Prozac



Prozac
Enhancement of the anticonvulsant effect of fluoxetine following blockade of 5-HT1A receptors.

Browning RA, Wood AV, Merrill MA, Dailey JW, Jobe PC.

Department of Physiology, Southern Illinois University School of Medicine, Carbondale, USA.

Serotonin reuptake inhibitors, such as fluoxetine, have been shown to exert anticonvulsant effects in several animal models of epilepsy. In view of recent studies showing that 5-HT1A receptor antagonists (somatodendritic autoreceptor antagonists) enhance the increase in extracellular 5-hydroxytryptamine (5-HT, serotonin) produced by serotonin reuptake inhibitors, it was of interest to determine if these antagonists also enhance the anticonvulsant effect of fluoxetine in Genetically Epilepsy-Prone Rats (GEPRs). The 5-HT1A receptor antagonists (-)-pindolol and LY 206130 (1-[1-H-indol-4-yloxy]-3-[cyclohexylamino]-2-propanol maleate) were examined in the present study and both enhanced the anticonvulsant action of fluoxetine in severe seizure GEPRs (GEPR-9s). The latter effect of LY 206130 was found to be dose- and 5-HT-dependent. These findings provide further evidence that the increase in extracellular serotonin observed after administering fluoxetine in combination with a 5-HT1A receptor antagonist is physiologically important and that the anticonvulsant effect of fluoxetine in the GEPR is mediated through an increase in extracellular 5-HT.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9384247&dopt=Abstract fluoxetine Prozac



Prozac
Evaluation of monoamine oxidase B inhibition by fluoxetine (Prozac): an in vitro and in vivo study.

Mukherjee J, Yang ZY.

Department of Radiology, Franklin McLean Institute, The University of Chicago, IL 60637, USA. j-mukherjee uchicago.edu

Inhibition of monoamine oxidase B was investigated both in vitro and in vivo in rats by using the radioligand, N-(6-[18F]fluorohexyl)-N-methylpropargylamine ([18F]FHMP). Binding affinities of five compounds, deprenyl, clorgyline, fluoxetine, norfluoxetine and citalopram were studied. Fluoxetine and norfluoxetine showed affinities of 17 and 13 microM for monoamine oxidase B, respectively. Acute doses of fluoxetine and norfluoxetine (20 mg/kg) also significantly inhibited (10 to 15%) the binding of the radioligand in vivo while citalopram showed lower affinity (140 microM) for monoamine oxidase B and little effect in vivo. The in vivo effects of the various drugs were directly comparable to their in vitro affinities for binding to monoamine oxidase B in the correlation plot of percent control in vivo binding of [18F]FHMP and binding affinity, -logIC50 (R2 = 0.989). These results provide evidence for a potential role of monoamine oxidase B inhibition in the therapeutic effects of Prozac.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9389388&dopt=Abstract fluoxetine Prozac



Prozac
Blockade of pre- and post-synaptic 5-HT1A receptors does not modify the effect of fluoxetine or 5-hydroxytryptophan on ethanol and food intake in rats.

Ciccocioppo R, Panocka I, Polidori C, Dourish CT, Massi M.

Department of Pharmacological Sciences and Experimental Medicine, University of Camerino, Italy.

Selective serotonin reuptake inhibitors (SSRIs) or serotonin precursors inhibit ethanol and food intake by increasing the synaptic availability of 5-HT in the central nervous system. However, these agents can also increase 5-HT levels at somatodendritic 5-HT1A autoreceptors, with negative effects on serotonergic transmission. (+)WAY100135 [N-ter-butyl 3-4-(2-methoxy-phenyl) piperazin-1-yl-2-phenylpropanamide dihydrochloride] is a selective antagonist both at pre- and post-synaptic 5-HT1A receptors. The present study investigated the effect on ethanol and food intake of (+)WAY100135, given alone or coadministered with the SSRI fluoxetine or the 5-HT precursor 5-hydroxytryptophan (5-HTP) in genetically selected alcohol-preferring rats. Blockade of presynaptic 5-HT1A receptors after injection of (+)WAY100135, 0.1 or 1 microgram/rat, into the dorsal raphe did not significantly modify ethanol, food or total fluid intake. The same doses of (+)WAY100135 did not modify the inhibition of ethanol and food intake induced by intraperitoneal (i.p.) injection of fluoxetine, 5 mg/kg. Subcutaneous (s.c.) administration of (+)WAY100135 (1 or 10 mg/kg) did not affect the 3-h, or the overnight intake of ethanol, food or total fluids. Given together with i.p. fluoxetine (5 mg/kg) or s.c. 5-HTP (100 mg/kg plus carbidopa. 12.5 mg/kg), the same s.c. doses of (+)WAY100135 did not modify their inhibitory effect on ethanol and food consumption. Present findings suggest that blockade either of pre- or of pre- and postsynaptic 5-HT1A receptors does not potentiate the inhibitory effect of fluoxetine or 5-HTP on ethanol and food intake.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9399367&dopt=Abstract fluoxetine Prozac



Prozac
Effect of fluoxetine on a neuronal, voltage-dependent potassium channel (Kv1.1).

Tytgat J, Maertens C, Daenens P.

Laboratory of Toxicology, University of Leuven, Belgium.

1. Fluoxetine (Prozac) is widely used as an antidepressant drug and is assumed to be a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (SSRI). Claims that its beneficial psychotropic effects extend beyond those in treatment of depression have drawn clinical and popular attention to this compound, raising the question of whether there is anything exceptional about the supposed selective actions. 2. We have used the voltage clamp technique to study the effect of fluoxetine on a neuronal, voltage-dependent potassium (K+) channel (RCK1; Kv1.1), expressed in p6nopus laevis oocytes. This channel subunit is abundantly expressed in the central nervous system and K+ channels containing this subunit are involved in the repolarization process of many types of neurones. 3. Blockade of the K+ currents by fluoxetine was found to be use- and dose-dependent. Wash-out of this compound could not be achieved. Fluoxetine did not affect the ion selectivity of this K+ channel, as the reversal potential was unaltered. 4. Slowing of both activation and deactivation kinetics of the channel by fluoxetine was observed, including tail current crossover upon repolarization. 5. Hodgkin-Huxley type of models and more generalized Markov chain models were used to fit the kinetics of the data. Based upon a Markov kinetic scheme, our data can be interpreted to mean that blockade of fluoxetine consists of two components: a voltage-independent occurring in the last closed, but available state of the channel, and a voltage-dependent occurring in the open state. 6. This study describes the first biophysical working model for the mechanism of action of fluoxetine on a neuronal, voltage-dependent K+ channel, RCK1. Although this channel is not very potently blocked by fluoxetine when expressed in oocytes, this study may help us to understand some of the clinical symptoms seen with elevated serum concentrations of this SSRI.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9421290&dopt=Abstract fluoxetine Prozac



Prozac
Assessment of the potential for a pharmacokinetic interaction between fluoxetine and terfenadine.

Bergstrom RF, Goldberg MJ, Cerimele BJ, Hatcher BL.

Eli Lilly and Company, Lilly Research Laboratories, Wishard Memorial Hospital, Indianapolis, IN 46202, USA.

OBJECTIVE: To assess whether fluoxetine and its metabolite, norfluoxetine, are inhibitors of the metabolism of CYP3A substrates. BACKGROUND: Because inhibition of the first-pass metabolism of terfenadine may be associated with fatal arrhythmia, we assessed the possibility that fluoxetine inhibits this metabolism as a model for CYP3A drug interactions. METHODS: Male subjects (n = 12) were given two single doses of 60 mg terfenadine alone (treatment 1) and again after the eighth dose in a 9-day regimen of 60 mg fluoxetine once a day (treatment 2). Blood samples, collected up to 48 hours after each terfenadine dose, were assayed for terfenadine and terfenadine acid metabolite. The assay limits of quantification were 0.1 ng/ml and 5.0 ng/ml, respectively. Noncompartmental pharmacokinetic data for terfenadine and terfenadine acid metabolite were compared between treatments. RESULTS: Mean value +/- SD plasma concentrations of fluoxetine (165 +/- 45 ng/ml) and norfluoxetine (83 +/- 23 ng/ml) achieved after the eighth dose did not cause a significant change in terfenadine acid metabolite pharmacokinetics. All terfenadine concentrations were less than 5 ng/ml and they were approximately 30% lower after fluoxetine pretreatment compared with terfenadine alone. The area under the concentration-time curve for terfenadine was lower after fluoxetine administration, a statistically significant difference, but the peak concentration of terfenadine was not significantly different. Because most antihistaminic activity after terfenadine administration is attributed to its acid metabolite, the small decrease in terfenadine concentration is not clinically significant. No subject discontinued the drugs because of an adverse event. CONCLUSION: Fluoxetine did not inhibit the metabolism of terfenadine and is unlikely to affect the metabolism of terfenadine or other drugs that are CYP3A substrates.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9433393&dopt=Abstract fluoxetine Prozac