Prozac
Increased noradrenaline efflux induced by local infusion of fluoxetine in the rat frontal cortex.

Hughes ZA, Stanford SC.

Department of Pharmacology, University College London, UK.

In microdialysis experiments in vivo, local infusion of either the selective serotonin reuptake inhibitor, fluoxetine, or the selective noradrenaline uptake inhibitor, desipramine, increased noradrenaline efflux in rat frontal cortex. Synaptosomal uptake of [3H]noradrenaline was used to test whether inhibition of uptake could contribute to this effect of fluoxetine. Low concentrations of fluoxetine were less effective than desipramine at inhibiting [3H]noradrenaline uptake; both compounds were more potent than the selective serotonin reuptake inhibitor, citalopram. To investigate whether this inhibition of uptake involved an action on noradrenergic neurones, experiments compared the effects of a noradrenergic lesion, induced by the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), on the inhibition of uptake by fluoxetine, desipramine and citalopram. The lesion reduced [3H]noradrenaline uptake in the presence of fluoxetine and citalopram but increased it in the presence of desipramine. The results suggest both that inhibition of noradrenaline uptake could contribute to the actions of fluoxetine and that a non-noradrenergic mechanisms is a target for this action.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8982723&dopt=Abstract fluoxetine Prozac



Prozac
Neurodevelopment of children exposed in utero to antidepressant drugs.

Nulman I, Rovet J, Stewart DE, Wolpin J, Gardner HA, Theis JG, Kulin N, Koren G.

Motherisk Program, Hospital for Sick Children and University of Toronto, ON, Canada.

BACKGROUND: Many women of reproductive age have depression, necessitating therapy with either a tricyclic antidepressant drug or a drug, such as fluoxetine, that inhibits the reuptake of serotonin. Whether these drugs affect fetal neurodevelopment is not known. METHODS: We studied the children of 80 mothers who had received a tricyclic antidepressant drug during pregnancy, 55 children whose mothers had received fluoxetine during pregnancy, and 84 children whose mothers had not been exposed during pregnancy to any agent known to affect the fetus adversely. The children's global IQ and language development were assessed between 16 and 86 months of postnatal age by age-appropriate Bayley Scales of Infant Development or the McCarthy Scales of Children's Abilities (for IQ) and the Reynell Developmental Language Scales. RESULTS: The mean (+/-SD) global IQ scores were 118+/-17 in the children of mothers who received a tricyclic antidepressant drug, 117+/-17 in those whose mothers received fluoxetine, and 115+/-14 in those in the control group. The language scores were similar in all three groups. The results were similar in children exposed to a tricyclic antidepressant drug or fluoxetine during the first trimester and those exposed throughout pregnancy. There were also no significant differences in temperament, mood, arousability, activity level, distractibility, or behavior problems in the three groups of children. CONCLUSIONS: In utero exposure to either tricyclic antidepressant drugs or fluoxetine does not affect global IQ, language development, or behavioral development in preschool children.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8995088&dopt=Abstract fluoxetine Prozac



Prozac
Effect of prenatal fluoxetine (Prozac) exposure on brain serotonin neurons in prepubescent and adult male rat offspring.

Cabrera-Vera TM, Garcia F, Pinto W, Battaglia G.

Department of Pharmacology and Experimental Therapeutics, Loyola University of Chicago, Stritch School of Medicine, Maywood, Illinois, USA.

The present study examines the consequences of prenatal fluoxetine exposure on brain serotonin [5-hydroxytryptamine (5-HT)] neurons in male offspring. Pregnant rats were administered either saline or fluoxetine (10 mg/kg s.c.) daily from gestational day 13 through gestational day 20. The biochemical status of brain 5-HT neurons was assessed in prepubescent and adult offspring by measuring 1) the 5-HT and 5-hydroxyindoleacetic acid content, 2) the density of [3H]paroxetine-labeled 5-HT uptake sites and 3) the ability of the 5-HT-releasing drug p-chloroamphetamine to reduce 5-HT content. Biochemical parameters were assessed in the frontal cortex, hypothalamus, hippocampus, striatum and midbrain. Comparative effects on dopamine and norepinephrine content in selected regions were also determined. Prenatal exposure to fluoxetine significantly reduced (-28%) 5-HT content in the frontal cortex of prepubescent but not adult male offspring. In contrast, in adult progeny prenatal fluoxetine exposure produced a significant decrease only in midbrain 5-HT content (-28%). In addition, p-chloroamphetamine markedly reduced 5-HT content in all brain regions examined, but the ability of p-chloroamphetamine to reduce 5-HT content was significantly attenuated only in the midbrain of adult progeny prenatally exposed to fluoxetine. No significant differences were observed between control and fluoxetine-exposed progeny with respect to brain 5-hydroxyindoleacetic acid content, the 5-hydroxyindoleacetic acid/5-HT ratio or the density of 5-HT uptake sites, regardless of the brain region examined or the age of the offspring. These data provide additional evidence that prenatal exposure to fluoxetine can produce limited, rather than global, changes in brain 5-HT neurons in male rat offspring and that the effects observed are region-specific and age-dependent. The potential functional consequences and clinical implications of these alterations in brain 5-HT systems remain to be elucidated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8996191&dopt=Abstract fluoxetine Prozac



Prozac
Combined actions of zinc and fluoxetine on nicotinic acetylcholine receptors.

Garcia-Colunga J, Vazquez-Gomez E, Miledi R.

Instituto de Neurobiologia, Universidad Nacional Autonoma de Mexico, Campus Juriquilla, Queretaro, Mexico. garciac inb.unam.mx

Zinc and nicotinic acetylcholine receptors (nAChRs) seem to be associated with major depression, and some antidepressants, including fluoxetine (Prozac), antagonize nAChRs. Therefore, a study was made of the modulation of neuronal alpha4beta4 and muscle alpha1beta1gammadelta nAChRs, expressing in oocytes, by the combined action of zinc and fluoxetine. At a holding potential of -60 mV, 200 microM zinc increased by 361% the currents elicited by acetylcholine (ACh currents) for alpha4beta4 and by 182% for alpha1beta1gammadelta nAChRs. In contrast, 5 microM fluoxetine reduced the ACh currents to 31% for alpha4beta4 and to 45% for alpha1beta1gammadelta nAChRs. Additionally, fluoxetine reduced more the ACh currents in the presence of zinc: to 17% for alpha4beta4 and to 19% for alpha1beta1gammadelta nAChRs, and after washing out the fluoxetine the ACh current did not recover its zinc-potentiated value. Moreover, when ACh-activated nAChRs were exposed first to fluoxetine and then zinc was added, the potentiating effect of zinc was very small for muscle nAChRs and was nil for neuronal receptors. Thus, the inhibiting effect of fluoxetine prevails over the potentiating action of zinc. Finally, the effects of both zinc and fluoxetine were voltage independent, indicating that these substances interact outside the ion channel. As fluoxetine nullifies the effects of zinc, it appears that both substances interact in the same site. These results should help understand better the roles played by zinc, antidepressants, nAChRs and their combination in brain functions and in the treatment of depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15354177&dopt=Abstract fluoxetine Prozac



Prozac
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.

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



Prozac
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.

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



Prozac
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.

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



Prozac
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.

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