Serotonin receptors: Subtypes, functional responses and therapeutic relevance

Saxena, Pramod R.

doi:10.1016/0163-7258(94)00005-n

Cited by 194 publications

(97 citation statements)

References 205 publications

(95 reference statements)

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“…The 5-HT 2 receptors are also involved in various mental disorders (Kalkman and Fozard 1991;Saxena 1995), including migraine headaches, anxiety, depression, schizophrenia, and obsessive-compulsive disorder. Accordingly, 5-HT 2 receptors are expressed in diverse tissues such as brain (frontal cortex, nucleus accumbens, and tuberculum olfactorium), vascular smooth muscle, and platelets.…”

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confidence: 99%

Development and Characterization of Monoclonal Antibodies Specific to the Serotonin 5-HT_2AReceptor

Yoder

Shih

et al. 1998

J Histochem Cytochem.

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SUMMARY Serotonin (5-hydroxytryptamine, 5-HT) mediates many functions of the central and peripheral nervous systems by its interaction with specific neuronal and glial receptors. Fourteen serotonin receptors belonging to seven families have been identified through physiological, pharmacological, and molecular cloning studies. Monoclonal antibodies (MAbs) specific for each of these receptor subtypes are needed to characterize their expression, distribution, and function in embryonic, adult, and pathological tissues. In this article we report the development and characterization of MAbs specific to the serotonin 5-HT 2A receptor. To generate MAbs against 5-HT 2A R, mice were immunized with the N-terminal domain of the receptor. The antigens were produced as glutathionine S-transferase (GST) fusion proteins in insect cells using a Baculovirus expression system. The hybridomas were initially screened by ELISA against the GST-5-HT 2A R recombinant proteins and subsequently against GST control proteins to eliminate clones with unwanted reactivity. They were further tested by Western blotting against recombinant GST-5-HT 2A R, rat and human brain lysate, and lysate from cell lines transfected with 5-HT 2A R cDNA. One of the MAbs G186-1117, which recognizes a portion of the 5-HT 2A R N-terminus, was selected for further characterization. G186-1117 reacted with a band of molecular size 55 kD corresponding to the predicted size of 5-HT 2A R in lysates from rat brain and a 5-HT 2A R-transfected cell line. Its specificity was further confirmed by adsorption of immunoreactivity with recombinant 5-HT 2A R but not with recombinant 5-HT 2B R and 5-HT 2C R. Rat brain sections and Schwann cell cultures were immunohistochemically labeled with this MAb. G186-1117 showed differential staining in various regions of the rat brain, varying from regions with no staining to regions of intense reactivity. In particular, staining of cell bodies and dendrites of the pyramidal neurons in the cortex was observed, which is in agreement with observations of electrophysiological studies. (J Histochem Cytochem 46:811-824, 1998)

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confidence: 99%

Development and Characterization of Monoclonal Antibodies Specific to the Serotonin 5-HT_2AReceptor

Yoder

Shih

et al. 1998

J Histochem Cytochem.

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“…Glutamate and serotonin (5HT) play critical roles in several of these states (LaMantia, 1995;Saxena, 1995). In addition, results from several labs have suggested that astrocytes may play a role in the control of circadian rhythmicity (Ewer et al, 1992;van den Pol et al, 1992;Servière, 1993, 1995;van den Pol and Dudek, 1993;Bennett and Schwartz, 1994;Prosser et al, 1994).…”

Section: Trans-(ϯ)-1-amino-13-cyclopentanedicarboxylate (100 -500 M)mentioning

confidence: 99%

“…Many 5HT receptors seem to be G-protein-coupled (Chilmonczyk, 1995;Saxena, 1995;Sleight et al, 1995). 5HT receptors have been localized in the SCN (Lovenberg et al, 1993), and 5HT agonists have been shown to modulate glutamatergic activity in the circadian system in vivo Srkalovic et al, 1994).…”

Section: Mglur-5ht Receptor Interactionsmentioning

confidence: 99%

Metabotropic Glutamate Receptor Activation Modulates Kainate and Serotonin Calcium Response in Astrocytes

1997

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Although metabotropic glutamate receptor (mGluR) modulation has been studied extensively in neurons, it has not been investigated in astrocytes. We studied modulation of glutamate-evoked calcium rises in primary astrocyte cultures using fura-2 ratiometric digital calcium imaging. Calcium plays a key role as a second messenger system in astrocytes, both in regulation of many subcellular processes and in long distance intercellular signaling. Suprachiasmatic nucleus (SCN) and cortical astrocytes showed striking differences in sensitivity to glutamate and to mGluR agonists, even after several weeks in culture. Kainate-evoked intracellular calcium rises were inhibited by concurrent application of the type I and II mGluR agonists quisqualate (10 M),. Inhibition mediated by L-CCG-I had longlasting effects (Ͼ45 min) in ϳ30% of the SCN astrocytes tested. The inhibition could be mimicked by the L-type calcium channel blocker nimodipine (1 M) as well as by protein kinase C (PKC) activators phorbol 12,13-dibutyrate (10 M) and phorbol 12-myristate 13-acetate (500 nM), and blocked by the PKC inactivator (Ϯ)-1-(5-isoquinolinesulfonyl)-2-methylpiperazine (200 M), suggesting a mechanism involving PKC modulation of L-type calcium channels. In contrast, mGluRs modulated serotonin (5HT)-evoked calcium rises through a different mechanism. The type III mGluR agonist L-2-amino-4-phosphonobutyrate consistently inhibited 5HT-evoked calcium rises, whereas in a smaller number of cells quisqualate and L-CCG-I showed both inhibitory and additive effects. Unlike the mGluR-kainate interaction, which required a pretreatment with an mGluR agonist and was insensitive to pertussis toxin (PTx), the mGluR modulation of 5HT actions was rapid and was blocked by PTx. These data suggest that glutamate, acting at several metabotropic receptors expressed by astrocytes, could modulate glial activity evoked by neurotransmitters and thereby influence the ongoing modulation of neurons by astrocytes.

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“…Accordingly, in vitro evidence strongly suggests that treatments that increase intracellular cAMP levels modulate endogenous SCN firing rhythms. This is an effect inconsistent with activity at the 5-HT 1A receptor, because this receptor is known to couple negatively to adenylate cyclase through an inhibitory G-protein; G i (Cooper et al 1996;Saxena 1995).Subsequent cloning efforts identified a novel serotonin receptor, type 7, which exhibits less than 40% homology with other known serotonin receptors (Bard et al 1993). Using [3H]-5-CT autoradiography and in situ hybridization (Waeber and Moskowitz 1995), the 5-HT 7 receptor and its mRNA were detected in relatively high densities in limbic areas, particularly the hypothalamus, hippocampus, amygdala, mammillary nuclei, and raphe nuclei, and also diffusely within the cortex, a localization that suggests that this receptor may be involved in the pathophysiology of affective disease (Gutafson et al 1996;Kupferman 1991;Plassat et al 1993;Ranson 1934).…”

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confidence: 99%

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confidence: 99%

Effects of Antidepressants on 5-HT7 Receptor Regulation in the Rat Hypothalamus

Mullins

Gianutsos

1999

Neuropsychopharmacology

146

101

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Recent evidence suggests that a novel serotonin receptor 5-HT 7 localized in the hypothalamus downregulates in response to treatment with the antidepressant fluoxetine (Sleight et al. 1995). This receptor has also been implicated in the regulation of circadian rhythms (Lovenberg et al. 1993). Here Depression may involve many possible abnormalities corresponding to multiple biological correlates of dysfunction or dysregulation in either one or several brain neurotransmitter systems (Cooper et al. 1996;Nair and Sharma 1989), a property that may contribute to the apparent disparity in symptomology and response to antidepressant therapy. The strict classical notions of neurotransmitter dysregulation hypotheses that associate depression with a deficiency of a vailable neurotransmitter or subresponsivity of mainly noradrenergic and/ or serotonergic receptor systems are recently being expanded to include disturbances in biological rhythm regulation. Impairment of the efficiency of rhythm maintenance or rhythm desynchronization has been suggested by many to lead to mental fatigue and depression (Goodwin et al. 1982;Hallonquist et al. 1986;Healy 1987;Partonen 1994;Schwartz 1993;Wirz-Justice and Campbell 1982;Wirz-Justice et al. 1995). Clinically, it has been extensively documented that the timing and structure of rhythms in physiological, behavioral, and endocrinological functions seem to be abnormal in depression (Coiro et al. 1993;Duncan 1996;File 1990;Kupfer 1995;Nair and Sharma 1989;Wehr et al. 1979). Furthermore, studies investigating the patterns of circadian rhythms of patients diagnosed with depression have been undertaken with the premise of disturbed rhythmicity as a central theme underlying the etiology of some affective disorders (Duncan 1996;Goodwin et al. 1982;Healy 1987;Siever and Davis, 1985;Souetre et al. 1988).Although melatonin is generally thought to be a primary modulator of circadian function through the suprachiasmatic nucleus (SCN) of the hypothalamus (Armstrong and Redman 1993;Binkley 1993;Cassone et al. 1993;Dubocovich 1991;Ibata et al. 1997;Reiter 1993; From the Bristol-Myers Squibb Company (ULM, ASE), Neuroscience Drug Discovery, Wallingford, Connecticut; and University of Connecticut, Department of Pharmaceutical Sciences (GG), Storrs, Connecticut, USA.Address correspondence to: U. Lena Mullins, Ph.D., BristolMyers Squibb Company, Neuroscience Drug Discovery, Department 408, 5 Research Parkway, Wallingford, Connecticut 06492, USA.Received January 1, 1999; revised March 23, 1999; accepted March 26, 1999. N EUROPSYCHOPHARMACOLOGY 1999 -VOL . 21 , NO . 3 Effects of Antidepressants 353 Stankov et al. 1993), the serotonergic system also plays a critical role in circadian modulation. The SCN receives dense projections from the raphe serotonergic neurons originating in the brainstem (Jacobs and Azmitia 1992;Meyer-Bornstein and Morin 1996;Van De Kar and Lorens 1979). Lesions of the median raphe serotonergic system using the neurotoxic agent 5,7-dihydroxytryptamine (5,7-DHT) produce a sever...

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Serotonin receptors: Subtypes, functional responses and therapeutic relevance

Cited by 194 publications

References 205 publications

Development and Characterization of Monoclonal Antibodies Specific to the Serotonin 5-HT_2AReceptor

Development and Characterization of Monoclonal Antibodies Specific to the Serotonin 5-HT_2AReceptor

Metabotropic Glutamate Receptor Activation Modulates Kainate and Serotonin Calcium Response in Astrocytes

Effects of Antidepressants on 5-HT7 Receptor Regulation in the Rat Hypothalamus

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Serotonin receptors: Subtypes, functional responses and therapeutic relevance

Cited by 194 publications

References 205 publications

Development and Characterization of Monoclonal Antibodies Specific to the Serotonin 5-HT2AReceptor

Development and Characterization of Monoclonal Antibodies Specific to the Serotonin 5-HT2AReceptor

Metabotropic Glutamate Receptor Activation Modulates Kainate and Serotonin Calcium Response in Astrocytes

Effects of Antidepressants on 5-HT7 Receptor Regulation in the Rat Hypothalamus

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Development and Characterization of Monoclonal Antibodies Specific to the Serotonin 5-HT_2AReceptor

Development and Characterization of Monoclonal Antibodies Specific to the Serotonin 5-HT_2AReceptor