Evidence for a role of 5-HT1C receptors in the antiserotonergic properties of some antidepressant drugs

doi:10.1016/0014-2999(93)90453-O

European Journal of Pharmacology

Volume 231, Issue 2, 9 February 1993, Pages 223-229

https://doi.org/10.1016/0014-2999(93)90453-O Get rights and content

Abstract

A variety of antidepressants of different chemical classes were tested for their in vivo and in vitro activity at 5-HT_1C receptors in the brain. Conventional tricylic antidepressants (imipramine, desipramine, maprotiline, clomipramine, trimipramine, amitriptyline, nortriptyline, doxepin, amoxapine) as well as mianserin and trazodone were found to display high to low nanomolar affinity for 5-HT_1C receptors. Antidepressants of other chemical classes and with other mechanisms of action (affecting amine uptake systems: fluoxetine, citalopram, setraline, fluvoxamine, nomifensine, amineptine; or monoamine oxidase inhibitors: moclobemide, iproniazid) had negligible affinities (micromolar range) for 5-HT_1C receptors, except fluoxetine. When tested in an in vivo rat model thought to reveal functional agonistic or antagonistic properties at 5-HT_1C receptors, all antidepressants displaying high affinity for this receptor type (except clomipramine and trimipramine) were antagonists at 5-HT_1C receptors. Antidepressants with a lower affinity for 5-HT_1C receptors (except nomifensine) were inactive in this functional in vivo model. Taken together, these results suggest that antagonism at brain 5-HT_1C receptors is a component of the antiserotonergic properties of a number of established antidepressants. In addition, the study confirmed that 5-HT_1A receptors functionally interact with 5-HT_1C receptors, which suggests that some degree of activity at 5-HT_1A receptors may also be an important property for antidepressant activity.

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Cited by (112)

Serotonergic modulation of the activity of mesencephalic dopaminergic systems: Therapeutic implications
2017, Progress in Neurobiology
Citation Excerpt :
5-HT2C receptors have raised interest in the case of antidepressants because 5-HT2C receptors bind several antidepressant drugs with submicromolar affinity (Jenck et al., 1998, 1994, 1993). In agreement, the penile erection induced by the non-selective agonist mCPP in rats, a behavioural response associated with central 5-HT2C receptors, is reduced by several antidepressant drugs (Jenck et al., 1998, 1994, 1993; Millan et al., 1997). Acute administration of amitriptyline and mianserin, two antidepressants with high affinity for 5-HT2C receptors, enhanced DA release in the rat NAc under specific conditions, likely due to blocking these receptor subtypes (Di Matteo et al., 2000c).
Since their discovery in the mammalian brain, it has been apparent that serotonin (5-HT) and dopamine (DA) interactions play a key role in normal and abnormal behavior. Therefore, disclosure of this interaction could reveal important insights into the pathogenesis of various neuropsychiatric diseases including schizophrenia, depression and drug addiction or neurological conditions such as Parkinson’s disease and Tourette’s syndrome. Unfortunately, this interaction remains difficult to study for many reasons, including the rich and widespread innervations of 5-HT and DA in the brain, the plethora of 5-HT receptors and the release of co-transmitters by 5-HT and DA neurons. The purpose of this review is to present electrophysiological and biochemical data showing that endogenous 5-HT and pharmacological 5-HT ligands modify the mesencephalic DA systems’ activity. 5-HT receptors may control DA neuron activity in a state-dependent and region-dependent manner. 5-HT controls the activity of DA neurons in a phasic and excitatory manner, except for the control exerted by 5-HT_2C receptors which appears to also be tonically and/or constitutively inhibitory. The functional interaction between the two monoamines will also be discussed in view of the mechanism of action of antidepressants, antipsychotics, anti-Parkinsonians and drugs of abuse.
5-HT2C receptors in psychiatric disorders: A review
2016, Progress in Neuro-Psychopharmacology and Biological Psychiatry
5-HT2Rs have a different genomic organization from other 5-HT2Rs. 5HT2CR undergoes post-transcriptional pre-mRNA editing generating diversity among RNA transcripts. Selective post-transcriptional editing could be involved in the pathophysiology of psychiatric disorders through impairment in G-protein interactions. Moreover, it may influence the therapeutic response to agents such as atypical antipsychotic drugs. Additionally, 5-HT2CR exhibits alternative splicing.
Central serotonergic and dopaminergic systems interact to modulate normal and abnormal behaviors. Thus, 5HT2CR plays a crucial role in psychiatric disorders. 5HT2CR could be a relevant pharmacological target in the treatment of neuropsychiatric disorders. The development of drugs that specifically target 5-HT2C receptors will allow for better understanding of their involvement in the pathophysiology of psychiatric disorders including schizophrenia, anxiety, and depression.
Among therapeutic means currently available, most drugs used to treat highly morbid psychiatric diseases interact at least partly with 5-HT2CRs. Pharmacologically, 5HT2CRs, have the ability to generate differentially distinct response signal transduction pathways depending on the type of 5HT2CR agonist. Although this receptor property has been clearly demonstrated, in vitro, the eventual beneficial impact of this property opens new perspectives in the development of agonists that could activate signal transduction pathways leading to better therapeutic efficiency with fewer adverse effects.
New therapeutic opportunities for 5-HT<inf>2C</inf> receptor ligands in neuropsychiatric disorders
2016, Pharmacology and Therapeutics
The 5-HT_2C receptor (R) displays a widespread distribution in the CNS and is involved in the action of 5-HT in all brain areas. Knowledge of its functional role in the CNS pathophysiology has been impaired for many years due to the lack of drugs capable of discriminating among 5-HT₂R subtypes, and to a lesser extent to the 5-HT_1B, 5-HT₅, 5-HT₆ and 5-HT₇Rs. The situation has changed since the mid-90s due to the increased availability of new and selective synthesized compounds, the creation of 5-HT_2C knock out mice, and the progress made in molecular biology. Many pharmacological classes of drugs including antipsychotics, antidepressants and anxiolytics display affinities toward 5-HT_2CRs and new 5-HT_2C ligands have been developed for various neuropsychiatric disorders. The 5-HT_2CR is presumed to mediate tonic/constitutive and phasic controls on the activity of different central neurobiological networks. Preclinical data illustrate this complexity to a point that pharmaceutical companies developed either agonists or antagonists for the same disease.
In order to better comprehend this complexity, this review will briefly describe the molecular pharmacology of 5-HT_2CRs, as well as their cellular impacts in general, before addressing its central distribution in the mammalian brain. Thereafter, we review the preclinical efficacy of 5-HT_2C ligands in numerous behavioral tests modeling human diseases, highlighting the multiple and competing actions of the 5-HT_2CRs in neurobiological networks and monoaminergic systems. Notably, we will focus this evidence in the context of the physiopathology of psychiatric and neurological disorders including Parkinson's disease, levodopa-induced dyskinesia, and epilepsy.
Pharmacology of serotonin and female sexual behavior
2014, Pharmacology Biochemistry and Behavior
Citation Excerpt :
Systemic treatment with ketanserin has been unequivocably associated with a decline in lordosis behavior (Hunter et al., 1985; Mendelson and Gorzalka, 1986c). Interestingly, the SSRI, fluoxetine also acts as a 5-HT2 receptor antagonist (Jenck et al., 1993; Palvimaki et al., 1996) so that 5-HT2 receptor effects may contribute to this antidepressant's ability to reduce lordosis behavior. When ketanserin was infused into the MBH, ketanserin inhibited lordosis behavior (Uphouse et al., 1996b) and effects were reversed by the relatively selective 5-HT2A/2C receptor agonist, DOI [(+/−)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl] (Wolf et al., 1998a).
In this review, first a historical perspective of serotonin's (5-HT) involvement in female sexual behavior is presented. Then an overview of studies implicating 5-HT is presented. The effect of drugs that increase or decrease CNS levels of 5-HT is reviewed. Evidence is presented that drugs which increase 5-HT have negative effects on female sexual behavior while a decrease in 5-HT is associated with facilitation of sexual behavior. Studies with compounds that act on 5-HT₁, 5-HT₂ or 5-HT₃ receptors are discussed. Most evidence indicates that 5-HT_1A receptor agonists inhibit sexual behavior while 5-HT₂ or 5-HT₃ receptors may exert a positive influence. There is substantial evidence to support a role for 5-HT in the modulation of female consummatory sexual behavior, but studies on the role of 5-HT in other elements of female sexual behavior (e.g. desire, motivation, sexual appetite) are few. Future studies should be directed at determining if these additional components of female sexual behavior are also modulated by 5-HT.
Controversies on the role of 5-HT<inf>2C</inf> receptors in the mechanisms of action of antidepressant drugs
2014, Neuroscience and Biobehavioral Reviews
Evidence from the various sources indicates alterations in 5-HT_2C receptor functions in anxiety, depression and suicide, and other stress-related disorders treated with antidepressant drugs. Although the notion of a 5-HT_2C receptor desensitization following antidepressant treatments is rather well anchored in the literature, this concept is mainly based on in vitro assays and/or behavioral assays (hypolocomotion, hyperthermia) that have poor relevance to anxio-depressive disorders. Our objective herein is to provide a comprehensive overview of the studies that have assessed the effects of antidepressant drugs on 5-HT_2C receptors. Relevant molecular (second messengers, editing), neurochemical (receptor binding and mRNA levels), physiological (5-HT_2C receptor-induced hyperthermia and hormone release), behavioral (5-HT_2C receptor-induced changes in feeding, anxiety, defense and motor activity) data are summarized and discussed. Setting the record straight about drug-induced changes in 5-HT_2C receptor function in specific brain regions should help to determine which pharmacotherapeutic strategy is best for affective and anxiety disorders.
Comparison of female Fischer and Sprague-Dawley rats in the response to ketanserin
2013, Pharmacology Biochemistry and Behavior
The effects of the 5-HT_2A/2C receptor antagonist, ketanserin, on lordosis behavior were examined in hormonally primed, ovariectomized Fischer and Sprague–Dawley females. Rats were primed with 0.067 μg/g body weight estradiol benzoate and 3.33 μg/g body weight progesterone. After a pretest for sexual behavior, rats were injected with 0.416 to 10 mg/kg ketanserin. In both strains, lordosis behavior, lordosis quality, and proceptivity were significantly reduced by ketanserin. There was modest evidence of a strain difference with Sprague–Dawley females slightly more sensitive to ketanserin. In a second experiment, the effects of 10 mg/kg fluoxetine, 1 mg/kg ketanserin, and their combination were examined to determine if the two drugs would have additive effects on sexual behavior. There was no evidence that the drugs were additive in their effect and the strains did not differ in their response to the combined treatment. These findings are discussed in relation to prior evidence for strain differences in the sexual behavioral response to fluoxetine and to a receptor agonist acting preferentially at 5-HT_1A receptors.

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European Journal of Pharmacology

Abstract

References (18)

Evidence that imipramine activates 5-HT_1C receptor function

Eur. J. Pharmacol.

Effects of antidepressant drugs on different receptors in the brain

Eur. J. Pharmacol.

The binding of serotonergic ligands to the porcine choroid plexus: characterization of a new type serotonin recognition site

Eur. J. Pharmacol.

Effects of antidepressants on serotonin-evoked current in Xenopus oocytes injected with rat brain m-RNA

Eur. J. Pharmacol.

Drug-induced penile erections in rats: indications of serotonin 1B receptor mediation

Eur. J. Pharmacol.

Behavioral evidence for functional interactions between 5-HT receptor subtypes in rats and mice

Br. J. Pharmacol.

Involvement of 5-HT_1C receptors in drug-induced penile erections in rats

Psychopharmacology

Fluoxetine familiarizes with a 5-HT_1C, but not with a 5-HT_1A -or 5 HT₂ receptor agonist

2nd Int. Symposium on Serotonin, from Cell Biology to Pharmacology and Therapeutics

Trazodone: a review of its pharmacological properties and therapeutic use in depression and anxiety

Drugs

Cited by (112)

Serotonergic modulation of the activity of mesencephalic dopaminergic systems: Therapeutic implications

5-HT2C receptors in psychiatric disorders: A review

New therapeutic opportunities for 5-HT<inf>2C</inf> receptor ligands in neuropsychiatric disorders

Pharmacology of serotonin and female sexual behavior

Controversies on the role of 5-HT<inf>2C</inf> receptors in the mechanisms of action of antidepressant drugs

Comparison of female Fischer and Sprague-Dawley rats in the response to ketanserin

Evidence for a role of 5-HT1C receptors in the antiserotonergic properties of some antidepressant drugs

Abstract

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Drug-induced penile erections in rats: indications of serotonin 1B receptor mediation

Eur. J. Pharmacol.

Behavioral evidence for functional interactions between 5-HT receptor subtypes in rats and mice

Br. J. Pharmacol.

Involvement of 5-HT1C receptors in drug-induced penile erections in rats

Psychopharmacology

Fluoxetine familiarizes with a 5-HT1C, but not with a 5-HT1A -or 5 HT2 receptor agonist

2nd Int. Symposium on Serotonin, from Cell Biology to Pharmacology and Therapeutics

Trazodone: a review of its pharmacological properties and therapeutic use in depression and anxiety

Drugs

Evidence for a role of 5-HT_1C receptors in the antiserotonergic properties of some antidepressant drugs

Involvement of 5-HT_1C receptors in drug-induced penile erections in rats

Fluoxetine familiarizes with a 5-HT_1C, but not with a 5-HT_1A -or 5 HT₂ receptor agonist