Blockage of 5HT<sub>2C</sub>serotonin receptors by fluoxetine (Prozac)

Yan, Ni; Miledi, Ricardo

doi:10.1073/pnas.94.5.2036

Cited by 167 publications

(89 citation statements)

References 31 publications

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“…The latter two were found only in DOI-treated animals. pre-mRNA editing suggests the possibility that the changes in 5-HT 2C pre-mRNA editing detected in fluoxetine-treated mice are attributable to the blockade of 5-HT 2C receptor activation by this drug (Ni and Miledi, 1997). However, more studies on mice treated with 5-HT 2A /2C -selective antagonist as well as different serotonin-selective reuptake inhibitors are needed to clarify this issue.…”

Section: Discussionmentioning

confidence: 99%

“…However, the actual synaptic concentration of 5-HT in the prefrontal cortex of depressed suicide victims is not known. Moreover, fluoxetine is also a competitive antagonist of 5-HT 2C receptors (Ni and Miledi, 1997), which could obscure the interpretation of the finding if signaling through 5-HT 2C receptors is involved in regulating 5-HT 2C pre-mRNA editing. Therefore, the present study sought to establish the precise nature of changes in editing-site preferences that occur in response to a sustained decrease in the concentration of synaptic 5-HT, as well as those that occur in response to a sustained activation of 5-HT 2A /2C receptors.…”

Section: Abstract: Serotonin; 5-ht 2c Receptor; Rna Editing; Forebramentioning

confidence: 99%

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Modulation of Serotonin 2C Receptor Editing by Sustained Changes in Serotonergic Neurotransmission

et al. 2002

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Serotonin 2C (5-HT 2C ) receptor pre-mRNA is a substrate for RNA editing enzymes that convert five adenosines (named A, B, CЈ, C, and D editing sites) to inosines. Editing of two of these sites (CЈ and C) is crucial for decreasing the efficiency of the receptor to activate G-protein. Nucleotide sequence analysis of mouse forebrain neocortical 5-HT 2C mRNA isoforms revealed that editing at these two sites is regulated in a serotonindependent manner. In serotonin-depleted mice, CЈ-and C-site editing is significantly decreased. This results in an increased expression of 5-HT 2C mRNA isoforms encoding receptors with higher sensitivity to serotonin. In contrast, a 4 d treatment with the 5-HT 2A/2C agonist (Ϯ)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane significantly increases the editing frequency at the CЈ site and leads to increased expression of 5-HT 2C mRNA isoforms encoding receptors that activate G-protein least efficiently. None of the drug treatments led to alterations in cytoplasmic 5-HT 2C mRNA levels. These data indicate that editing of 5-HT 2C pre-mRNA is a mechanism that retains basic response properties of 5-HT 2C receptors in the face of changing synaptic input to keep receptor activation within an optimal range for information processing. Key words: serotonin; 5-HT 2C receptor; RNA editing; forebrain neocortex; 5-HT depletion; 5-HT 2A/2C agonistThe conversion of adenosine (A) to inosine (I) by ADARs (adenosine deaminases that act on RNA) is the most widespread editing in higher eukaryotes (Bass, 2002). Although the total inosine content of rat brain poly(A ϩ ) RNA predicts that one inosine occurs approximately once every 17,000 nucleotides (Paul and Bass, 1998), only a few neuronal substrates for A to I editing have been identified. They include the serotonin 2C (5-HT 2C ) receptor, the first G-protein-coupled receptor known to be edited. In 5-HT 2C pre-mRNA, a total of five closely spaced adenosines (named A, B, CЈ, C, and D editing sites) located within a sequence that encodes the second intracellular loop of the receptors protein can be converted to inosines (Burns et al., 1997;Niswender et al., 1999). This editing can change up to three triplet codons and has the potential to generate 24 different protein isoforms. Compared with nonedited 5-HT 2C receptors, the receptor isoform that results from editing at the ABCD sites and other partially edited isoforms that are edited at the CЈsite but not the C site exhibit a fourfold reduction in the efficiency to activate G-protein in response to agonist stimulation. This reduction is even higher (15-to 25-fold) for completely edited isoforms and other partially edited isoforms that are edited at both CЈ and C sites. Other partially edited isoforms that are not edited at the CЈ and/or C site appear to be fully functional (Niswender et al., 1999;Wang et al., 2000).At present, the significance of 5-HT 2C pre-mRNA editing in vivo is still unknown. However, a recent study indicates that this editing is regulated and suggests that this regulation is sensitive ...

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Section: Discussionmentioning

confidence: 99%

Section: Abstract: Serotonin; 5-ht 2c Receptor; Rna Editing; Forebramentioning

confidence: 99%

Modulation of Serotonin 2C Receptor Editing by Sustained Changes in Serotonergic Neurotransmission

et al. 2002

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“…mianserin, nefazadone) bind with high affinity to 5-HT2 receptors, receptors that have been implicated in the regulation of DA systems (Millan, 2005). In fact, the prototypical SSRI fluoxetine is a 5-HT2C antagonist (Ni and Miledi, 1997). Alterations in 5-HT2C receptors have also been observed in suicide victims (Niswender et al, 2001).…”

Section: Depression/anxietymentioning

confidence: 99%

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Alex

Pehek

2007

Pharmacology & Therapeutics

536

311

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The neurotransmitter dopamine (DA) has a long association with normal functions such as motor control, cognition, and reward, as well as a number of syndromes including drug abuse, schizophrenia, and Parkinson's disease. Studies show that serotonin (5-HT) acts through several 5-HT receptors in the brain to modulate DA neurons in all three major dopaminergic pathways. There are at least 14 5-HT receptor subtypes, many of which have been shown to play some role in mediating 5-HT/DA interactions. Several subtypes, including the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3 and 5-HT4 receptors, act to facilitate DA release, while the 5-HT2C receptor mediates an inhibitory effect of 5-HT on DA release. Most 5-HT receptor subtypes only modulate DA release when 5-HT and/or DA neurons are stimulated, but the 5-HT2C receptor, characterized by high levels of constitutive activity, inhibits tonic as well as evoked DA release. This review summarizes the anatomical evidence for the presence of each 5-HT receptor subtype in dopaminergic regions of the brain and the neuropharmacological evidence demonstrating regulation of each DA pathway. The relevance of 5-HT receptor modulation of DA systems to the development of therapeutics used to treat schizophrenia, depression, and drug abuse is discussed. Lastly, areas are highlighted in which future research would be maximally beneficial to the treatment of these disorders.

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“…Induction of specific genes (e.g., c-fos) has been elicited with a single exposure to antidepressants (Dahmen et al 1997;Beck 1995;Muck-Seler et al 1996). Fluoxetine has also been shown directly to alter membrane currents from the 5-HT receptors with acute administration (Pitt et al 1994;Ni and Miledi 1997); this is a distinctly different action from its classic effect of inhibiting presynaptic serotonin reuptake transporters, but could affect EEG signals. The contribution of these early changes to the clinical response in depressed humans remains to be fully understood.…”

Section: Commentmentioning

confidence: 99%

Early Changes in Prefrontal Activity Characterize Clinical Responders to Antidepressants

Cook¹,

Leuchter

Morgan

et al. 2002

Neuropsychopharmacology

182

169

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Previous studies have shown that changes in brain functionClinicians long have observed a lag time of several weeks between the initiation of antidepressant treatment and clinical response for many patients (Hyman and Nestler 1996;Katz et al. 1996). Some individuals do have early symptomatic improvement, and this has been reported to predict further improvement over the next several weeks (Nierenberg et al. 1995). Reports have suggested that some physiologic changes are seen shortly after initiation of treatment (Sulser 1989;Beck 1995;Dahmen et al. 1997). No clinically practical physiologic predictor of treatment response has yet been identified with these techniques, however, and the relationship of early physiologic changes to eventual clinical outcome remains incompletely understood.Quantitative electroencephalography (QEEG) has been used as a physiologic measure in efforts to address these questions. Prior work with "pharmaco-EEG" techniques has shown that the administration of antidepressant compounds yields reproducible changes in EEG activity in healthy control subjects within a few hours of dosing (Saletu et al. 1982(Saletu et al. , 1983(Saletu et al. , 1986(Saletu et al. , 1987(Saletu et al. , 1987 Grunberger 1985, 1988;Sannita et al. 1983;Sannita 1990; Early Prefrontal Changes in Depression 121Itil et al. 1984;Herrmann et al. 1991;Luthringer et al. 1996). The relationship of these immediate EEG changes in control subjects to eventual clinical response in a depressed population is unclear. Other QEEG work with depressed subjects has found that changes from baseline in theta power early in the course of treatment may characterize groups of depressed patients who are more likely to respond to antidepressant treatment (Ulrich et al. 1994). Unfortunately, the overlap in the value of these changes between responder and nonresponder groups precluded the use of this measure in response prediction for individual subjects, and prior research did not indicate how to relate changes in theta power to other measures of regional brain activity (e.g., regional cerebral blood flow or metabolism). We previously have shown that absolute and relative power are complementary measures of brain activity (Leuchter et al. 1993). A relatively new QEEG measure, "cordance," combines information from both absolute and relative power measures (Leuchter et al. 1994a(Leuchter et al. , 1994b. The algorithm yields two indicators: a categorical value ("concordant" or "discordant" state) and a numerical value for each electrode. In an earlier report with the categorical measure , we observed that depressed subjects exhibiting the concordant state prior to treatment had better treatment outcomes when treated with fluoxetine than did subjects with the discordant state. In this report, we use the num*erical values of cordance, because they allow examination of changes in regional brain activity with treatment. In validation against data collected simultaneously with [H 2 15O]-positron emission tomography (PET), cordance values in the the...

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Blockage of 5HT_2Cserotonin receptors by fluoxetine (Prozac)

Abstract: Fluoxetine (

Cited by 167 publications

References 31 publications

Modulation of Serotonin 2C Receptor Editing by Sustained Changes in Serotonergic Neurotransmission

Modulation of Serotonin 2C Receptor Editing by Sustained Changes in Serotonergic Neurotransmission

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Early Changes in Prefrontal Activity Characterize Clinical Responders to Antidepressants

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Blockage of 5HT2Cserotonin receptors by fluoxetine (Prozac)

Abstract: Fluoxetine (

Cited by 167 publications

References 31 publications

Modulation of Serotonin 2C Receptor Editing by Sustained Changes in Serotonergic Neurotransmission

Modulation of Serotonin 2C Receptor Editing by Sustained Changes in Serotonergic Neurotransmission

Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

Early Changes in Prefrontal Activity Characterize Clinical Responders to Antidepressants

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Product

Resources

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Blockage of 5HT_2Cserotonin receptors by fluoxetine (Prozac)