Research reportMechanism of action of serotonin selective reuptake inhibitors: Serotonin receptors and pathways mediate therapeutic effects and side effects
Introduction
This article will explore hypotheses to explain the diverse actions of serotonin selective reuptake inhibitors (SSRIs). Two main hypotheses will be explored here. Firstly, the wide variety of therapeutic actions and side effects of the SSRIs may be mediated by specific receptor subtypes and discrete pathways for serotonin throughout the central nervous system, and in the case of certain side effects, throughout the body. Secondly, the explanation for delayed therapeutic effects characteristic of SSRIs may be found in delayed neurochemical adaptations. The explanation for the delayed development of tolerance to side effects of SSRIs also may be found in delayed neurochemical adaptations.
Section snippets
Topography for serotonin's actions: receptor subtypes and unique projection pathways
Do different post-synaptic serotonin receptor subtypes mediate different physiological actions of serotonin? Serotonin has long been known to mediate (probably with other neurotransmitters) such diverse behaviors as mood, anxiety, sleep, temperature, appetite, sexual behavior, eating behavior, movements, gastrointestinal (GI) motility, and many more (Aghajanian, 1995, Brown and van Praag, 1991, Cowen, 1991, Dubovsky, 1994, Glennon and Duckat, 1995, Jacobs and Fornal, 1995, Keppel Hesselink and
Initiating actions of SSRIs
Inhibition of the neuronal transporter for serotonin has long been established as one of the mechanisms of action of numerous antidepressants (Barker and Blakely, 1995, Feighner and Boyer, 1996, Leonard, 1996, Stahl, 1996). The introduction of several agents more selective for this action over any other pharmacologic effect has created a new and well known class of antidepressants called SSRIs (e.g., see Feighner and Boyer, 1996).
Hyman and Nestler (1996) have proposed that acute, short term
General overview
Since it generally takes time for the numerous therapeutic actions of the SSRIs to develop or for the side effects of the SSRIs to abate (Feighner and Boyer, 1996), this has led to a search for delayed neurobiological actions of the SSRIs which might explain their delayed pharmacological actions. One such delayed action of the SSRIs is the desensitization of 5HT1A and 5HT2A receptors (Charney et al., 1981, Charney et al., 1991, Leonard, 1995, Leonard, 1996, Stahl, 1992, Stahl, 1994, Stahl, 1996
Topography for SSRI therapeutic actions and side effects
Serotonin projections and pathways as mediators of specific therapeutic effects of SSRIs. The therapeutic actions demonstrated by SSRIs are of course not limited to antidepressant actions (Feighner and Boyer, 1996, Stahl, 1996), but also include therapeutic utility in panic disorder (Ballenger, 1996), obsessive–compulsive disorder (Stein and Hollander, 1996) and bulimia (Curzon, 1991, Pijl et al., 1991, Walsh and Devlin, 1995). The possible anatomic substrates for these actions are illustrated
Conclusions
A crude topography of serotonin functioning in its different pathways and at its various receptor subtypes is beginning to crystallize from ongoing experiments. To the extent that these findings comprise hypotheses, they may generate experiments to prove or refute them. To the extent that these are mere speculations, they will hopefully lead to cogent hypotheses better formulated for experimental testing as knowledge of the serotonin systems and receptors advances.
The plethora of well
Acknowledgements
Figures adapted and reproduced from S.M. Stahl, Essential Psychopharmacology, Cambridge University Press, New York, 1996, with permission. Grant support: this work was supported in part by NIMH research grant No. 5 RO1 MH45787-02 and by a VA Merit Review Award to Dr. Stahl. This work was also supported in part by Mental Health Clinical Research Center grant No. MH30914 and by General Clinical Research Center grant No. MO1-RR00827 to UCSD.
References (131)
- et al.
The effects of ondansetron, a 5HT3 antagonist, on cognition in rodents and primates
Pharmacol. Biochem. Behav.
(1990) - et al.
Fluvoxamine preferentially increases extracellular 5HT in the raphe nuclei: an in vivo microdialysis study
Eur. J. Pharmacol.
(1992) - et al.
Clinical evaluation of 5HT3 receptor antagonist as antiemetics
Trends Pharmacol. Sci.
(1991) - et al.
Stimulation of hippocampal 5HT1A receptors causes amnesia and anxiolytic-like but not antidepressant-like effects in the rat
Eur. J. Pharmacol.
(1993) - et al.
The psychopharmacology of 5HT3 receptors
Pharmacol. Ther.
(1990) - et al.
Alteration of serotonin release in the guinea pig orbito-frontal cortex by selective serotonin reuptake inhibitors – relevance to treatment of obsessive–compulsive disorder
Neuropsychopharmacology
(1995) - et al.
Short-term fluoxetine treatment alters monoamine levels and turnover in discrete brain nuclei
Brain Res.
(1994) Minireview: uptake inhibitors increase extracellular serotonin concentration measured by brain microdialysis
Life Sci.
(1994)- et al.
Ipsapirone, a 5HT1A agonist, suppresses REM sleep equally in depressed patients and normal controls
Neuropsychopharmacology
(1996) - et al.
Lack of 5HT1A autoreceptor desensitization following chronic citalopram treatment, as determined by in vivo microdialysis
Neuropharmacology
(1994)
Species differences in the pharmacology of terminal 5HT autoreceptors in mammalian brain
Trends Pharmacol. Sci.
Citalopram's ability to increase the extracellular concentrations of serotonin in the dorsal raphe prevents the drug's effect in the frontal cortex
Brain Res.
Quantitative autoradiographic mapping of serotonin receptors in the brain. I. Serotonin 1 receptors
Brain Res.
Quantitative autoradiographic mapping of serotonin receptors in the brain. I. Serotonin 2 receptors
Brain Res.
Differential effects of clomipramine given locally or systemically on extracellular 5HT in raphe nuclei and frontal cortex: an in vivo microdialysis study
Naunyn-Schniedeberg's Arch. Pharmacol.
5HT1A receptor antagonists in combination therapy: 5HT and antidepressants: new views from microdialysis studies
Trends Pharmacol. Sci.
The 5-HT3 antagonist ondansetron reduces gastrointestinal side effects induced by a specific serotonin re-uptake inhibitor in man
J. Psychopharmacol.
Development of β-adrenergic receptor subsensitivity by antidepressants
Nature
Caudate glucose metabolic rate changes with both drug and behavior therapy for obsessive–compulsive disorder
Arch. Gen. Psychiat.
Reduction of prefrontal cortex glucose metabolism common to three types of depression
Arch. Gen. Psychiat.
Independent regulation of β-1 and β-2 adrenoceptors
Br. J. Pharmacol.
Chronic treatment with fluvoxamine increases extracellular serotonin in frontal cortex but not in raphe nuclei
Synapse
Cisapride for the treatment of nausea produced by selective serotonin reuptake inhibitors
Am. J. Psychiat.
5HT2 antagonist ritanserin in neuroleptic induced Parkinsonism: a double blind comparison with orphenadrine and placebo
Clin. Neuropharmacol.
Electrophysiological investigations on the effect of repeated zimelidine administration on serotonergic neurotransmission in the rat
J. Neurosci.
Modifications of the serotonin system by antidepressant treatment: implications for the therapeutic response in major depression
J. Clin. Psychopharmacol.
Differential properties of pre- and post-synaptic 5-hydroxytryptamine 1A receptors: I. Effect of spiperone
J. Pharmacol. Exp. Ther.
Differential properties of pre- and postsynaptic 5-hydroxytryptamine 1A receptors: II. Effect of pertussis and cholera toxins
J. Pharmacol. Exp. Ther.
Decreased beta-adrenergic receptors in rat brain after chronic administration of the selective serotonin uptake inhibitor fluoxetine
Psychopharmacology
Effects of a selective 5HT reuptake blocker, citalopram, on the sensitivity of 5HT autoreceptors: electrophysiological studies in the rat brain
Nauyn-Schmiedeberg's Arch. Pharmacol.
Presynaptic and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments – an in vivo electrophysiological study in the rat
Neuropsychopharmacology
Receptor sensitivity and the mechanism of action of antidepressant treatment: implications for the etiology and therapy of depression
Arch. Gen. Psychiatr.
Advances in 5HT1A antagonist research
Drugs Future
Serotonin receptor subtypes: implications for psychopharmacology
Br. J. Psychiatry
Electrophysiological evidence for a large receptor reserve for inhibition of dorsal raphe cell firing by 5HT1A agonists
Synapse
5HT1A receptors, depression, and anxiety
Pharmacol. Biochem. Behav.
Electrophysiological studies on the effects of long term reuptake inhibition of the function of 5HT neurons
Clin. Neuropharmacol.
Cited by (431)
Dysfunction of neurotransmitter metabolism is associated with the severity of depression in first-diagnosed, drug-naïve depressed patients
2024, Journal of Affective DisordersProtective effects of SSRI, Citalopram in mutant APP and mutant Tau expressed dorsal raphe neurons in Alzheimer's disease
2024, Biochimica et Biophysica Acta - Molecular Basis of DiseaseMajor depressive disorder as a neuro-immune disorder: Origin, mechanisms, and therapeutic opportunities
2023, Neuroscience and Biobehavioral ReviewsNeurochemical mechanisms of deep brain stimulation for depression in animal models
2023, European Neuropsychopharmacology
- 1
Dr. Stahl is a consultant, speaker and grant recipient of each company which manufactures SSRIs (Lilly, Pfizer, Smith Kline, Forest, Solvay) as well as many of their competitors (Janssen, Bayer, Yamanouchi, Glaxo–Wellcome, Wyeth-Ayerst, Bristol Myers Squibb, Roche, Ciba-Geigy, Pharmacia-Upjohn), but not a major stockholder in any. Dr. Stahl is also a consultant and recipient of stock options for a small biotechnology company in San Diego, Neurocrine Biosciences.