Modulation of Dopamine Transmission by 5HT2C and 5HT3 Receptors: A Role in the Antidepressant Response

Dremencov, Eliyahu; Weizmann, Yifat; Kinor, Noa; Gispan-Herman, Iris; Yadid, Gal

doi:10.2174/138945006775515491

Cited by 69 publications

(53 citation statements)

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“…In a previous study (23), a polymorphism in the regulatory region of HTR3A shown to increase gene expression (24) was found to affect the improvement observed in depressed patients upon paroxetine treatment. In addition, other studies have suggested a link between 5-HT 3 receptor activation and the treatment/ etiology of depression (5,(25)(26)(27). Our data in combination with the association study by Yamada et al (20) suggest that the role of the 5-HT 3AB receptor in the etiology and treatment of depression may be interesting to investigate in greater detail.…”

Section: Discussionsupporting

confidence: 79%

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High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT _3AB receptor

Krzywkowski

Davies

Feinberg-Zadek

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The 5-hydroxytryptamine-3 (5-HT3) receptor mediates the fast excitatory neurotransmission of serotonin and is known to mediate the nausea/emesis induced by radio/chemotherapy and anesthetics. A polymorphism encoding the variation Y129S in the 5-HT3B subunit exists in high frequency in the general population and has been shown to be inversely correlated to the incidence of major depression in women. We show that 5-HT3AB(Y129S) receptors exhibit a substantially increased maximal response to serotonin compared with WT receptors in two fluorescence-based cellular assays. In electrophysiological recordings, the deactivation and desensitization kinetics of the 5-HT3AB ( 5-HT3 ͉ ligand-gated ion channel ͉ polymorphism ͉ serotonin ͉ receptor kinetics S erotonin [5-hydroxytryptamine (5-HT)] is a major neurotransmitter in both the CNS and the peripheral nervous system (PNS), where it plays a key role in basic functions such as mood, sleep, appetite regulation, and libido (1). Serotonergic signaling is mediated via a plethora of G protein-coupled receptors, whereas only one serotonin-gated ion channel has been identified: the 5-HT 3 receptor (2).5-HT 3 receptors are expressed in both the CNS and the PNS. Presynaptic 5-HT 3 receptors are known to modulate the synaptic release of various neurotransmitters (3-5), whereas postsynaptic 5-HT 3 receptors are responsible for the fast excitatory response to serotonin (6). The role of the 5-HT 3 receptor in general physiology and pathophysiology is not well established. However, the 5-HT 3 receptor is known to mediate the nausea and emesis caused by radio/chemotherapy and anesthetics (7). Furthermore, 5-HT 3 antagonists have proven effective in the treatment of irritable bowel disease (7). Finally, the 5-HT 3 receptor has been suggested to be involved in anxiety, depression, pain, alcohol dependence, and eating disorders (7,8).The 5-HT 3 receptor is a nonselective cation channel belonging to the superfamily of Cys-loop ligand-gated ion channels that includes receptors for the neurotransmitters ACh, ␥-aminobutyric acid, and glycine. These receptors are pentameric assemblies, where the five subunits form a central ion channel path (9). To date, five 5-HT 3 subunits have been cloned: 5-HT 3A -5-HT 3E (10-12). Transcripts of 5-HT 3A , 5-HT 3B , and 5-HT 3C subunits have been demonstrated in both the CNS and the PNS (11-13), whereas 5-HT 3D and 5-HT 3E transcripts have been detected only in peripheral tissues (12). By using 5-HT 3B -specific antibodies, the existence of the 5-HT 3B subunit in the human hippocampus (14) as well as in the CNS in rodents (15) has been confirmed. Whereas homomeric 5-HT 3A receptors are functional, the other subunits only form functional receptors when coexpressed with 5-HT 3A (11,16). The homomeric 5-HT 3A and the heteromeric 5-HT 3AB receptors are the best characterized 5-HT 3 receptors, whereas the physiological relevance of subunits 5-HT 3c -5-HT 3E has just started to be unraveled. In heterologous expression systems, the 5-HT 3A :5-HT 3B stoichiometry an...

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Section: Discussionsupporting

confidence: 79%

“…Presynaptic 5-HT 3 receptors are known to modulate the synaptic release of various neurotransmitters (3)(4)(5), whereas postsynaptic 5-HT 3 receptors are responsible for the fast excitatory response to serotonin (6). The role of the 5-HT 3 receptor in general physiology and pathophysiology is not well established.…”

mentioning

confidence: 99%

High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT _3AB receptor

Krzywkowski

Davies

Feinberg-Zadek

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, our results suggest that an imbalance in the mesolimbic GABA-ergic system together with the alterations in DHEA levels may lead to the pathological behavioral outcomes observed in the FSL rats. The GABA-ergic system is an important regulator of dopaminergic neurons (Akiyama et al, 2004), which are relevant to depression (Dremencov et al, 2006;Friedman et al, 2007). Specifically, GABA A Rs within the VTA regulate dopamine output to the NAc (Bankson and Yamamoto, 2004;Yan et al, 2004), suggesting a modulatory role for these receptors in depression (Garcia-Alloza et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

DHEA Lessens Depressive-Like Behavior via GABA-ergic Modulation of the Mesolimbic System

Genud

Merenlender

Gispan-Herman

et al. 2008

Neuropsychopharmacol

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Alterations in the levels of dehydroepiandrosterone (DHEA) in the brain can allosterically modulate g-aminobutyric-acid-type-A (GABA A R), N-methyl-D-aspartate (NMDAR), and Sigma-1 (s1R) receptors. In humans, DHEA has antidepressive effects; however, the mechanism is unknown. We examined whether alterations in DHEA also occur in an animal model of depression, the Flinders-sensitiveline (FSL) rats, with the intention of determining the brain site of DHEA action and its antidepressant mechanism. We discovered that DHEA levels were lower in some brain regions involved with depression of FSL rats compared to Sprague-Dawley (SD) controls. Moreover, DHEA (1 mg/kg IP for 14 days)-treated FSL rats were more mobile in the forced swim test than FSL controls. In the NAc and VTA, significant changes were observed in the levels of the d-subunit of GABA A , but not of s1R mRNA, in FSL rats compared to SD rats. The d-subunit controls the sensitivity of the GABA A R to the neurosteroid. Indeed, treatment (14 days) of FSL rats with the GABA A agonist muscimol (0.5 mg/kg), together with DHEA (a negative modulator of GABA A ), reversed the effect of DHEA on immobility in the swim test. Perfusion of DHEA sulfate (DHEAS) (3 nM and 30 nM for 14 days) into the VTA and NAc of FSL rats improved their performance in the swim test for at least 3 weeks post-treatment. Our results imply that alterations in DHEA are involved in the pathophysiology of depression and that the antidepressant action of DHEA is mediated via GABA A Rs in the NAc and VTA.

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“…Conceivably, increasing 5-HT after CART peptides would activate 5-HT receptors. To date, at least fourteen subtypes of 5-HT receptors have been identified, including 5-HT 1B , 5-HT 2A , 5-HT 2C and 5-HT 3 receptors in the NAcc (Bruinvels et al 1993;Dremencov et al 2006;Ma et al 2006). Neurologically, NAcc, which belongs to dopaminergic mesolimbic and mesocortical systems, is associated with hedonic and motivational actions such as drug rewarding and reinforcement.…”

mentioning

confidence: 99%

“…However, the NAcc is emerged to play a role in depressive behavior because of the intimated interaction between dopaminergic systems and 5-HT receptors found in this region (Elhwuegi 2004). Activation of 5-HT receptors may lead to an increase in dopamine (Boulenguez et al 1998;Yan and Yan 2001) and possibly potentiate a therapeutic effect of antidepressants (Dremencov et al 2006). It is very possible that the effect can be enhanced after activation of serotonergic neurons in the DRN.…”

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confidence: 99%

CART peptides increase 5-hydroxytryptamine in the dorsal raphe and nucleus accumbens of freely behaving rats

Ma¹,

Pearson²,

Tao³

2007

Neuroscience Letters

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Cocaine and amphetamine-regulated transcript peptides (CART) are implicated in the antidepressant effect. This may involve in 5-hydroxytryptamine (5-HT) in the CNS. The aim of the present studies was to investigate the effect of CART peptides on extracellular 5-HT in the dorsal raphe nucleus (DRN) and nucleus accumbens (NAcc) using a microdialysis approach in freely-behaving rats. Reverse infusion of CART in the DRN produced a concentration (10 µM-100 µM) -dependent increase in 5-HT in the DRN. Similarly, CART [62][63][64][65][66][67][68][69][70][71][72][73][74][75][76] (10 µM-100 µM) infused into the DRN and NAcc elevated 5-HT in the DRN and NAcc, respectively. Thus, CART increases extracellular 5-HT in both the DRN and NAcc. In addition, infusion of CART [62][63][64][65][66][67][68][69][70][71][72][73][74][75][76] (100 µM) in the DRN produced a significant increase in 5-HT in the NAcc, implying an existence of CART receptors responsible for the depolarization-dependent release. In summary, the results of the present studies suggest that CART peptides may have an antidepressant effect through increases in extracellular 5-HT. KeywordsCART peptides; antidepressant; dorsal raphe; nucleus accumbens; microdialysis; serotonin Cocaine-and amphetamine-regulated transcript peptides (CART) are a group of brainderived substances induced by the administration of cocaine and amphetamine, and they are widely distributed throughout the brain including the dorsal raphe nucleus (DRN) and nucleus accumbens (NAcc) (Douglass et al. 1995;Hurd and Fagergren 2000;Koylu et al. 1998). The peptides are stored within the vesicles (Damaj et al. 2003), and thus may act as a neuromodulator (Smith et al. 1999). Physiologically, CART peptides produced hypophagia, hyperlocomotion and anxiety-like behavior (Chaki et al. 2003;Kimmel et al. 2000;Stanek 2006). At high doses, CART also induced analgesia and impaired locomotion (Damaj et al. 2003 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. CART (Chaki et al. 2003). Increases in 5-hydroxytryptamine (5-HT; serotonin) turnover was implicated in the regulation of CART-induced hypophagia (Choi et al. 2003). Recently, it was found that patients with CART mutation had high depression scores, supporting a speculation that CART may have an antidepressant effect, probably through 5-HT in the brain (Miraglia del Giudice et al. 2006;Pae et al. 2006). NIH Public AccessTo understand the role of CART in depression, the aim of the present studies was to determine extracellular 5-HT in response to CART administration in freely-behaving rats. The experiments were...

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Modulation of Dopamine Transmission by 5HT2C and 5HT3 Receptors: A Role in the Antidepressant Response

Cited by 69 publications

References 0 publications

High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT _3AB receptor

High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT _3AB receptor

DHEA Lessens Depressive-Like Behavior via GABA-ergic Modulation of the Mesolimbic System

CART peptides increase 5-hydroxytryptamine in the dorsal raphe and nucleus accumbens of freely behaving rats

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Modulation of Dopamine Transmission by 5HT2C and 5HT3 Receptors: A Role in the Antidepressant Response

Cited by 69 publications

References 0 publications

High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT 3AB receptor

High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT 3AB receptor

DHEA Lessens Depressive-Like Behavior via GABA-ergic Modulation of the Mesolimbic System

CART peptides increase 5-hydroxytryptamine in the dorsal raphe and nucleus accumbens of freely behaving rats

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High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT _3AB receptor

High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT _3AB receptor