Classics in Chemical Neuroscience: Fluoxetine (Prozac)

Wenthur, Cody J.; Bennett, Megan R.; Lindsley, Craig W.

doi:10.1021/cn400186j

Cited by 80 publications

(71 citation statements)

References 90 publications

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“…However, as Clz is a broad-spectrum ligand (Wenthur et al, 2014), at present its specific mechanism of action in Rasd2 KOs is still unclear. One possibility is that Clz could normalize DAergic-mediated signaling in these mice, thereby preventing their abnormal gating disturbances.…”

Section: Rasd2 Regulates Psychotomimetic Drug Effects D Vitucci Et Almentioning

confidence: 99%

Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and ‘Schizophrenia-Like Behaviors’ in Mice

Vitucci

Giorgio

Napolitano

et al. 2015

Neuropsychopharmacol

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Rasd2 is a thyroid hormone target gene, which encodes for a GTP-binding protein enriched in the striatum where, among other functions, it modulates dopaminergic neurotransmission. Here we report that human RASD2 mRNA is abundant in putamen, but it also occurs in the cerebral cortex, with a distinctive expression pattern that differs from that present in rodents. Consistent with its localization, we found that a genetic variation in RASD2 (rs6518956) affects postmortem prefrontal mRNA expression in healthy humans and is associated with phenotypes of relevance to schizophrenia, including prefrontal and striatal grey matter volume and physiology during working memory, as measured with magnetic resonance imaging. Interestingly, quantitative real-time PCR analysis indicated that RASD2 mRNA is slightly reduced in postmortem prefrontal cortex of patients with schizophrenia. In the attempt to uncover the neurobiological substrates associated with Rasd2 activity, we used knockout mice to analyze the in vivo influence of this G-protein on the prepulse inhibition of the startle response and psychotomimetic drug-related behavioral response. Data showed that Rasd2 mutants display deficits in basal prepulse inhibition that, in turn, exacerbate gating disruption under psychotomimetic drug challenge. Furthermore, we documented that lack of Rasd2 strikingly enhances the behavioral sensitivity to motor stimulation elicited by amphetamine and phencyclidine. Based on animal model data, along with the finding that RASD2 influences prefronto-striatal phenotypes in healthy humans, we suggest that genetic mutation or reduced levels of this G-protein might have a role in cerebral circuitry dysfunction underpinning exaggerated psychotomimetic drugs responses and development of specific biological phenotypes linked to schizophrenia.

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Section: Rasd2 Regulates Psychotomimetic Drug Effects D Vitucci Et Almentioning

confidence: 99%

Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and ‘Schizophrenia-Like Behaviors’ in Mice

Vitucci

Giorgio

Napolitano

et al. 2015

Neuropsychopharmacol

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“…However, not all studies report behavioral changes in the offspring of mothers taking SSRIs during pregnancy (Casper et al, 2003;Misri et al, 2006). Furthermore, although the first SSRI to be prescribed in the United States, fluoxetine, has now been available for 25 years (Wenthur et al, 2014), no studies have examined the long-term behavioral consequences for adult offspring of mothers who took this drug during pregnancy.…”

Section: Introductionmentioning

confidence: 99%

Perinatal vs Genetic Programming of Serotonin States Associated with Anxiety

Altieri

Yang

O'Brien

et al. 2014

Neuropsychopharmacol

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Large numbers of women undergo antidepressant treatment during pregnancy; however, long-term consequences for their offspring remain largely unknown. Rodents exposed to serotonin transporter (SERT)-inhibiting antidepressants during development show changes in adult emotion-like behavior. These changes have been equated with behavioral alterations arising from genetic reductions in SERT. Both models are highly relevant to humans yet they vary in their time frames of SERT disruption. We find that anxiety-related behavior and, importantly, underlying serotonin neurotransmission diverge between the two models. In mice, constitutive loss of SERT causes life-long increases in anxiety-related behavior and hyperserotonemia. Conversely, early exposure to the antidepressant escitalopram (ESC; Lexapro) results in decreased anxiety-related behavior beginning in adolescence, which is associated with adult serotonin system hypofunction in the ventral hippocampus. Adult behavioral changes resulting from early fluoxetine (Prozac) exposure were different from those of ESC and, although somewhat similar to SERT deficiency, were not associated with changes in hippocampal serotonin transmission in late adulthood. These findings reveal dissimilarities in adult behavior and neurotransmission arising from developmental exposure to different widely prescribed antidepressants that are not recapitulated by genetic SERT insufficiency. Moreover, they support a pivotal role for serotonergic modulation of anxiety-related behavior.

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“…12 This evidence suggests that the (S)-enantiomer of fluoxetine 1 is more active in the inhibition of serotonin than the (R)-enantiomer. 12 Additionally, one of the major metabolites of fluoxetine 1, norfluoxetine (demethylated fluoxetine), is significantly more active as an inhibitor. In contrast, duloxetine 2 is marketed as a single (S)-enantiomer.…”

Section: Introductionmentioning

confidence: 99%

Total synthesis of fluoxetine and duloxetine through an in situ imine formation/borylation/transimination and reduction approach

2014

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We report efficient, catalytic, asymmetric total syntheses of both (R)-fluoxetine and (S)-duloxetine from α,β-unsaturated aldehydes conducting five sequential one-pot steps (imine formation/copper mediated β-borylation/transimination/reduction/oxidation) followed by the specific ether group formation which deliver the desired products (R)-fluoxetine in 45% yield (96% ee) and (S)-duloxetine in 47% yield (94% ee).

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Classics in Chemical Neuroscience: Fluoxetine (Prozac)

Cited by 80 publications

References 90 publications

Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and ‘Schizophrenia-Like Behaviors’ in Mice

Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and ‘Schizophrenia-Like Behaviors’ in Mice

Perinatal vs Genetic Programming of Serotonin States Associated with Anxiety

Total synthesis of fluoxetine and duloxetine through an in situ imine formation/borylation/transimination and reduction approach

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