Repeated administration of milnacipran induces rapid desensitization of somatodendritic 5-HT1A autoreceptors but not postsynaptic 5-HT1A receptors

Mochizuki, Daisuke; Hokonohara, Tadami; Kawasaki, Koh; Miki, Naomasa

doi:10.1177/026988110201600311

Cited by 26 publications

(15 citation statements)

References 45 publications

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“…During this period, 5-HT1A autoreceptors desensitize (Le Poul et al, 1995; Mochizuki et al, 2002; Shen et al, 2002; Elena Castro et al, 2003), leading to reduced 5-HT1A RNA and autoreceptor levels, particularly in animal models of depression and depressed subjects (Welner et al, 1989; Fanelli and McMonagle-Strucko, 1992; Sibug et al, 1998; Le Poul et al, 2000; Meltzer et al, 2004; Rabiner et al, 2004; Berney et al, 2008), resulting in restoration of raphe firing activity and 5-HT release. Chronic antidepressant treatment reverses changes in 5-HT1A receptor RNA expression in chronic stress models (Burnet et al, 1995; Greenwood et al, 2003, 2005; Morley-Fletcher et al, 2004), as well as in depression (Lopez et al, 1998; Lopez-Figueroa et al, 2004).…”

Section: -Ht1a Receptors In Depressionmentioning

confidence: 99%

“…Other compounds that act at 5-HT1A receptors, such as atypical antipsychotics aripiprazole (Abilify) or SNRI milnacipran (Savella), can also ameliorate response to SSRIs. However, while these compounds desensitize the 5-HT1A autoreceptor (Mochizuki et al, 2002), they have other targets that can participate in their antidepressant actions. In addition it is important to note that drugs that indirectly target 5-HT neurons (Guiard et al, 2008) such as bupropion or α2-adrenergic receptor antagonists may also enhance response to SSRI response (Tremblay and Blier, 2006; Trivedi et al, 2006a; Blier et al, 2010).…”

Section: Targeting 5-ht1a Autoreceptors For Antidepressant Responsementioning

confidence: 99%

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Modifying 5-HT1A receptor gene expression as a new target for antidepressant therapy

Albert¹

2010

Front. Neurosci.

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Major depression is the most common form of mental illness, and is treated with antidepressant compounds that increase serotonin (5-HT) neurotransmission. Increased 5-HT1A autoreceptor levels in the raphe nuclei act as a “brake” to inhibit the 5-HT system, leading to depression and resistance to antidepressants. Several 5-HT1A receptor agonists (buspirone, flesinoxan, ipsapirone) that preferentially desensitize 5-HT1A autoreceptors have been tested for augmentation of antidepressant drugs with mixed results. One explanation could be the presence of the C(−1019)G 5-HT1A promoter polymorphism that prevents gene repression of the 5-HT1A autoreceptor. Furthermore, down-regulation of 5-HT1A autoreceptor expression, not simply desensitization of receptor signaling, appears to be required to enhance and accelerate antidepressant action. The current review focuses on the transcriptional regulators of 5-HT1A autoreceptor expression, their roles in permitting response to 5-HT1A-targeted treatments and their potential as targets for new antidepressant compounds for treatment-resistant depression.

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Section: -Ht1a Receptors In Depressionmentioning

confidence: 99%

Section: Targeting 5-ht1a Autoreceptors For Antidepressant Responsementioning

confidence: 99%

Modifying 5-HT1A receptor gene expression as a new target for antidepressant therapy

Albert¹

2010

Front. Neurosci.

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“…The serotonin-1A (5-HT1A) receptor negatively regulates the activity of 5-HT neurons, and is expressed both as a presynaptic autoreceptor on raphe neurons, and as a major postsynaptic receptor in hippocampal, cortical, and hypothalamic regions involved in mood, emotion and stress response (Barnes and Sharp, 1999; Aznar et al, 2003; Varnas et al, 2004). Both presynaptic and postsynaptic 5-HT1A receptors have been implicated in the therapeutic mechanism of antidepressants: specifically, 5-HT1A autoreceptors are desensitized by chronic treatment with selective serotonin reuptake inhibitors (SSRIs) with no perceptible changes in postsynaptic 5-HT1A receptors (Mochizuki et al, 2002; Giovacchini et al, 2005). This desensitization is thought to increase the firing rate of 5-HT neurons with a concomitant increase in 5-HT neurotransmission (Blier and deMontigny, 1994; Stahl, 1998; Pineyro and Blier, 1999; Parsons et al, 2001) and tonic activation of postsynaptic neurons (Haddjeri et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of the serotonin 1 A transcriptional modulators five prime repressor element under dual repression-1 and nuclear-deformed epidermal autoregulatory factor by chronic stress

Iyo¹,

Kieran²,

Chandran³

et al. 2009

Neuroscience

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Chronic stress is known to affect brain areas involved in learning and emotional responses. These changes, thought to be related to the development of cognitive deficits are evident in major depressive disorder (MDD) and other stress related pathophysiologies. The serotoninrelated transcription factors ((Freud-1/CC2D1A; five prime repressor element under dual repression/coiled-coil C2 domain-1A and NUDR/Deaf-1; nuclear deformed epidermal autoregulatory factor) are two important regulators of the 5HT1A receptor. Using Western blotting and quantitative real-time polymerase chain reaction (qPCR) we examined the expression of mRNA and proteins for Freud-1, NUDR, and the 5-HT1A receptor in the prefrontal cortex (PFC) of male rats exposed to chronic restraint stress (CRS; 6h/day for 21 days). After 21 days of CRS, significant reductions in both Freud-1 mRNA and protein were observed in the prefrontal cortex (PFC) (36.8% and 32% respectively; p<0.001) while the levels of both NUDR protein and mRNA did not change significantly. Consistent with reduced Freud-1 protein, 5-HT1A receptor mRNA levels were equally upregulated in the PFC, while protein levels actually declined, suggesting post-transcriptional receptor downregulation. The data suggest that CRS produces distinct alterations in the serotonin system specifically altering Freud-1 and the 5-HT1A receptor in the PFC of the male rat while having no effect on NUDR. These results point to the importance of understanding the mechanism for the differential regulation of Freud-1 and NUDR in the PFC as a basis for understanding the related effects of chronic stress on the serotonin system (serotonin-related transcription factors) and stress-related disorders like depression.

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“…Repeated administration of milnacipran for at least 7 days has been found, using electrophysiological techniques, to significantly attenuate the potency of 5-HT to inhibit the firing of serotonergic neurons in the raphe nucleus while inhibition of the CA1 field potential by 5-HT in the hippocampus is not modified (Mochizuki et al 2002b). This suggests that milnacipran rapidly desensitizes presynaptic somatodendritic 5-HT 1A receptors but not postsynaptic 5-HT 1A receptors.…”

Section: Basic Studiesmentioning

confidence: 99%

Japanese experience with milnacipran, the first serotonin and norepinephrine reuptake inhibitor in Japan

Higuchi¹,

Briley²

2007

Neuropsychiatric Disease and Treatment

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Milnacipran is a serotonin and norepinephrine reuptake inhibitor (SNRI), with a balanced potency for the inhibition of the reuptake of the two monoamines. In this, it contrasts with venlafaxine and duloxetine which, while possessing a dual action, have a selectivity of the order of 30-fold and 10-fold respectively for the reuptake of serotonin. Milnacipran has mainly been launched in countries where the selective serotonin reuptake inhibitors (SSRIs) and venlafaxine had been established for several years. As such it has attracted relative little interest from clinician investigators as a research tool. Japan, however, represents a unique situation because in 1999 milnacipran was launched within months of the fi rst SSRI and is still the only SNRI in Japan together with only two SSRIs (a third has just been introduced). This has led to a large number of investigative clinical studies, many of which give interesting insights into the potential of milnacipran in the treatment of depression and of other disorders. This article reviews these Japanese studies with milnacipran.

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Repeated administration of milnacipran induces rapid desensitization of somatodendritic 5-HT1A autoreceptors but not postsynaptic 5-HT1A receptors

Cited by 26 publications

References 45 publications

Modifying 5-HT1A receptor gene expression as a new target for antidepressant therapy

Modifying 5-HT1A receptor gene expression as a new target for antidepressant therapy

Differential regulation of the serotonin 1 A transcriptional modulators five prime repressor element under dual repression-1 and nuclear-deformed epidermal autoregulatory factor by chronic stress

Japanese experience with milnacipran, the first serotonin and norepinephrine reuptake inhibitor in Japan

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