A review of the role of serotonin receptors in psychiatric disorders

Naughton, Marie; Mulrooney, Jane B.; Leonard, Brian E.

doi:10.1002/1099-1077(200008)15:6<397::aid-hup212>3.0.co;2-l

Cited by 227 publications

(78 citation statements)

References 129 publications

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“…These results are in line with predictions from the simulations, given the common view of depression as involving 5-HT 1A hypoactivity (Naughton et al, 2000). Ipsapirone shifts persons with depression from the low side of the inverted U-curve in Figure 3c to the right and upward, leading to better recall.…”

Section: -Ht and Memory M Meeter Et Alsupporting

confidence: 88%

“…In our discussion of the ipsapirone study, we relied on the hypothesis that hypoactivity of 5-HT 1A receptors causes part or all of the memory deficits seen in depression. Based on our results and known 5-HT dysregulation in depression (Naughton et al, 2000), we find this a defendable hypothesis, although more evidence is clearly needed to link memory deficits in depression to 5-HT with any certainty.…”

Section: Discussionmentioning

confidence: 57%

“…Hypofunction of the 5-hydroxytryptamine (5-HT) system has emerged as a leading candidate cause for depression (Naughton et al, 2000;Middlemiss et al, 2002). At the same time, several lines of evidence point to a role for 5-HT in memory (Buhot et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Effects of 5-HT on Memory and the Hippocampus: Model and Data

Meeter

Talamini

Schmitt

et al. 2005

Neuropsychopharmacol

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5-Hydroxytryptamine (5-HT) transmission has been implicated in memory and in depression. Both 5-HT depletion and specific 5-HT agonists lower memory performance, while depression is also associated with memory deficits. The precise neuropharmacology and neural mechanisms underlying these effects are unknown. We used neural network simulations to elucidate the neuropharmacology and network mechanisms underlying 5-HT effects on memory. The model predicts that these effects are largely dependent on transmission over the 5-HT 1A and 5-HT 3 receptors, which regulate the selectivity of retrieval. It also predicts differential memory deficit profiles for 5-HT depletion and overactivation. The latter predictions were confirmed in studies with healthy and depressed participants undergoing acute tryptophan depletion or ipsipirone challenge. The results suggest that the memory impairments in depressed subjects may be related to 5-HT undertransmission, and support the notion that 5-HT 1A agonists ameliorate memory deficits in depression. INTRODUCTIONHypofunction of the 5-hydroxytryptamine (5-HT) system has emerged as a leading candidate cause for depression (Naughton et al, 2000;Middlemiss et al, 2002). At the same time, several lines of evidence point to a role for 5-HT in memory (Buhot et al, 2000). Most prominently, depletion of tryptophan (TRP), a precursor of 5-HT, is associated with lower performance on episodic memory retention tests in humans (Riedel et al, 1999). This mirrors findings in depression, which is accompanied by moderate to severe memory deficits (Johnson and Magaro, 1987;Schaub et al, 2003). However, manipulations that increase 5-HT concentration or 5-HT receptor activation also lower memory performance, as indicated by receptor agonist studies in both humans (Riedel et al, 2002) and animals (Altman and Normile, 1988). Up to now, it is not known why both increased and decreased 5-HT activation have adverse effects on memory.5-HT binds to a large and disparate family of CNS receptors, which have effects that are sometimes opposite. Thus, many effects of different receptors seem to cancel each other out. In a review (see Supplementary Information on internet), we identify two robust effects of 5-HT in the hippocampus. First, 5-HT exerts a hyperpolarizing influence on principal cells; directly, via 5-HT 1A receptors, and indirectly, via facilitation of GABA release from local interneurons through 5-HT 3 receptors (Burnet et al, 1995;Piguet and Galvan, 1994). Activation of 5-HT 2A and 5-HT 2C receptors has been suggested to induce depolarization in principal cells (Piguet and Galvan, 1994;Barnes and Sharp, 1999), but these effects appear to be dominated by the depolarizing effects of 5-HT, as bath application of 5-HT will hyperpolarize principal cells in slice preparations of the dentate gyrus (Piguet and Galvan, 1994). In addition, through 5-HT 2C , 5-HT 4 , and 5-HT 7 receptors, afterhyperpolarizing (AHP) currents are downregulated, leading to reduced adaptation in principal cells (Torres et al, 1996;Bac...

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Section: -Ht and Memory M Meeter Et Alsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 57%

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Effects of 5-HT on Memory and the Hippocampus: Model and Data

Meeter

Talamini

Schmitt

et al. 2005

Neuropsychopharmacol

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“…The actions of 5-HT are mediated by 16 types and subtypes of receptors. 5 As the 5-HTergic system is assumed to be a modulatory system, the exact function of 5-HT is not easy to define. 6 However, 5-HT is known to be involved in many physiological and behavioral processes, including mood, appetite, sleep, activity, suicide, sexual behavior and cognition; all of which are affected in depression.…”

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confidence: 99%

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

et al. 2006

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In recent years, the term serotonergic vulnerability (SV) has been used in scientific literature, but so far it has not been explicitly defined. This review article attempts to elucidate the SV concept. SV can be defined as increased sensitivity to natural or experimental alterations of the serotonergic (5-HTergic) system. Several factors that may disrupt the 5-HTergic system and hence contribute to SV are discussed, including genetic factors, female gender, personality characteristics, several types of stress and drug use. It is explained that SV can be demonstrated by means of manipulations of the 5-HTergic system, such as 5-HT challenges or acute tryptophan depletion (ATD). Results of 5-HT challenge studies and ATD studies are discussed in terms of their implications for the concept of SV. A model is proposed in which a combination of various factors that may compromise 5-HT functioning in one person can result in depression or other 5-HT-related pathology. By manipulating 5-HT levels, in particular with ATD, vulnerable subjects may be identified before pathology initiates, providing the opportunity to take preventive action. Although it is not likely that this model applies to all cases of depression, or is able to identify all vulnerable subjects, the strength of the model is that it may enable identification of vulnerable subjects before the 5-HT related pathology occurs. Molecular Psychiatry ( Keywords: serotonin; mood disorders; stress; genetics; sex; tryptophan Involvement of serotonin in depressionMood disorders are one of the most prevalent forms of mental illness. 1 According to the DSM-IV, the lifetime risk for major depressive disorder is between 10 and 25% for women and between 5 and 12% for men. 2 Depression has been studied intensively during the last few decades, but the psychological and neurobiological determinants of depression have not yet been precisely defined. Although several factors are known to contribute to the etiology of depression, it is not clear how these factors cause depression, and why some subjects become depressed while others remain unaffected. In terms of biological factors in the etiology of depression, there are several hypotheses. These include neurotransmitter dysfunctions (serotonin, 5-HT; dopamine, DA; norepinephrine, NE); dysregulations in hypothalamic-pituitary-adrenal (HPA) axis activity; and immune system imbalance. The aim of this article is not to discuss all of these hypotheses in detail, but to evaluate the role that serotonin may play within these hypothesized mechanisms.It is widely accepted that diminished serotonergic (5-HTergic) function is involved in the onset and course of depression. 3,4 The 5-HTergic system is a large and complex system. Although nearly all cell bodies of 5-HTergic neurons are located in the raphe nuclei in the brain stem, the axons of these neurons innervate almost the entire brain. The actions of 5-HT are mediated by 16 types and subtypes of receptors. 5 As the 5-HTergic system is assumed to be a modulatory system, the exact func...

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“…Monoamine-based antidepressants, fortuitously discovered from clinical observations in the 1950s, represent a milestone in the treatment of depression [6,70,71] . Moreover, they provide clues to the biological basis of depression.…”

Section: Monoamine-based Antidepressants Restore Neural Plasticitymentioning

confidence: 99%

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

et al. 2014

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Depression is a devastating psychiatric disorder widely attributed to defi cient monoaminergic signaling in the central nervous system. However, most clinical antidepressants enhance monoaminergic neurotransmission with little delay but require 4−8 weeks to reach therapeutic efficacy, a paradox suggesting that the monoaminergic hypothesis of depression is an oversimplifi cation. In contrast to the antidepressants targeting the monoaminergic system, a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid (within 2 h) and sustained (over 7 days) antidepressant effi cacy in treatment-resistant patients. Glutamatergic transmission mediated by NMDARs is critical for experience-dependent synaptic plasticity and learning, processes that can be modifi ed indirectly by the monoaminergic system. To better understand the mechanisms of action of the new antidepressants like ketamine, we review and compare the monoaminergic and glutamatergic antidepressants, with emphasis on neural plasticity. The pathogenesis of depression may involve maladaptive neural plasticity in glutamatergic circuits that may serve as a new class of targets to produce rapid antidepressant effects.Keywords: depression; stress; neural plasticity; glutamatergic transmission; monoamine-based antidepressant; ketamine IntroductionDepression is a common psychiatric disorder, with prevalence rates of 19% in Beirut and 16.2% in the UnitedStates [1] . Depression is also one of the leading causes of severe mental disability, suicide, and socioeconomic burden, and its diagnosis sometimes relies on selfreported symptoms in the major depressive inventory [2,3] .The pathogenesis of depression is still not clear, and currently available antidepressants are far from satisfactory.Most antidepressants target the monoaminergic system [4] ; however, 30%-40% of patients are resistant to monoaminebased antidepressants (remittance rates of 13% to 36.8% with citalopram [5] ), and a clinically significant reduction of depressive symptoms in responders usually requires 4−8 weeks of daily treatment [6] . These limitations result in a large proportion of patients at high risk of suicide even after diagnosis. Thus, it is necessary to search for new antidepressants outside the monoaminergic system. R ecent clinical studies have demonstrated that a single dose of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine has rapid antidepressant efficacy within 2 h that can be sustained for over 7 days in patients with treatment-resistant depression [7,8] . This finding suggests that depression could be directly associated with defi cits in glutamatergic synaptic transmission and plasticity. The monoaminergic hypothesis of depression, based on the efficacy of antidepressants that enhance monoaminergic transmission and signaling, has dominated the field of depression research for nearly half a century.However, the primacy of monoaminergic dysfunction in depression is inconsistent with the delay between enhancement of synaptic monoamines confer...

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A review of the role of serotonin receptors in psychiatric disorders

Cited by 227 publications

References 129 publications

Effects of 5-HT on Memory and the Hippocampus: Model and Data

Effects of 5-HT on Memory and the Hippocampus: Model and Data

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

Rapid-onset antidepressant efficacy of glutamatergic system modulators: The neural plasticity hypothesis of depression

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