The Role of Serotonin in Depression

CHAPTER 4.2

The Role of Serotonin in Depression Gregory V. Carr and Irwin Lucki* Departments of Psychiatry and Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Abstract: A substantial body of research has developed concerning the role of serotonin (5-HT) in the etiology and treatment of major depressive disorder (MDD). The first section of this chapter summarizes the clinical evidence implicating alterations of the serotonergic system in the etiology of MDD. A general serotonin vulnerability has been proposed as a major risk factor in MDD, consisting of the composite risk factors from different components of 5-HT transmission. The effects of abnormal 5-HT synthesis, receptor function and genetic polymorphisms are discussed. The second section reviews some of the preclinical models and tests that are used to measure depressive behaviors and the efficacy of antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRIs). This section is focused on models that are commonly used in rodent species. Models and tests that require either acute or chronic antidepressant administration to achieve behavioral alterations are covered. The third section reviews the preclinical (rodent) literature concerning the role of individual 5-HT receptors in the development and pharmacological treatment of depressive behaviors. The effects of 5-HT depletion and of manipulation of the 5-HT transporter are also discussed. Although identifying the 5-HT receptors that support the therapeutic effects of SSRIs may lead to the development of more effective antidepressant drugs with fewer side effects, it is unclear whether the complete antidepressant effect of SSRIs can be reproduced by a single selective 5-HT receptor agonist or antagonist. Keywords: depression, antidepressants, SSRIs, models of depression, knockout mice, serotonin, rat, psychiatry.

This chapter will consider in turn the roles for 5-HT in causing major depressive disorder (MDD) and the role of 5-HT mechanisms underlying therapeutic treatment. Efforts to attribute the cause of depression to deficient 5-HT transmission stem from a historical literature that measured changes in the metabolism of 5-HT in patients with MDD. More sophisticated techniques are now available for clinical studies that have allowed the association of MDD with specific genes related to a family of 5-HT-related targets, and the imaging of specific 5-HT receptors in patients. This literature will be reviewed in brief because it is too large to be contained in this chapter. Among the frontline class of antidepressant treatments, selective serotonin reuptake inhibitors (SSRIs) exhibit their primary pharmacological effects through manipulation of the 5-HT system. SSRIs produce many adaptations that may be involved in their clinical efficacy. Preclinical studies have attempted to identify particular 5-HT receptor subtypes associated with antidepressant behavioral responses, with the goal of eventually providing targeted treatments. Genetically modified animals have been studied as models of developmental genetic vulnerability, and

Introduction Since the identification of iproniazid, an early antidepressant, as a monoamine oxidase inhibitor (MAOI) that prevents the degradation of serotonin (5-HT), the role of the serotonergic system in the etiology and treatment of depression has been an intense area of study. In the years since this discovery, many advances have been made in our understanding of the components of the serotonergic system. At least 14 serotonin receptor subtypes belonging to seven major families have been identified in the brain, each associated with distinct topographical distributions and cell signaling mechanisms. The nuclei of serotonin-producing neurons in the hindbrain and midbrain have been identified, and their axonal projections have been mapped (Barnes and Sharp, 1999). In addition to detailed molecular and anatomical information, there is a large body of behavioral and pharmacological data that has served to solidify the link between different components of the 5-HT system and depressive behavior. *

Corresponding author E-mail: [email protected] Christian Müller & Barry Jacobs (Eds.) Handbook of Behavioral Neurobiology of Serotonin ISBN 978-0-12-374634-4

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DOI: 10.1016/B978-0-12-374634-4.00030-7 Copyright 2010 Elsevier B.V. All rights reserved

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to elucidate the mechanism of action of SSRIs. This literature will be covered in the second part of this chapter.

Serotonin in the etiology of depression A variety of evidence has accumulated suggesting that deficits in 5-HT neurotransmission can contribute to the development of MDD. The earliest evidence reported decreased levels of 5-HT metabolites in the cerebrospinal fluid (CSF) of depressed patients, but much of the association may actually have been based on suicidal behavior rather than depression (Asberg, 1997; Placidi et al., 2001). Also, several reports found that the availability of L-tryptophan in plasma was significantly lower in subjects with MDD (Cowen et al., 1989; Maes et al., 1990), suggesting an overall reduction of 5-HT metabolism. Depletion of tryptophan, and lowering of brain 5-HT, can cause transient depressive symptoms in individuals that are vulnerable to depression, based on their personal or family history of depression (Moreno et al., 1999; Neumeister et al., 2004). In recently remitted depressed patients receiving SSRIs, acute tryptophan depletion led to a rapid clinically significant return of depressive symptoms (Delgado et al., 1999). In contrast, remitted depressed patients maintained with tricyclic antidepressants were less prone to relapse following tryptophan depletion. Although these findings suggested that the synthesis of 5-HT is necessary for the maintenance of remission induced by SSRIs, they are also consistent with the evocation of transient withdrawal symptoms following chronic SSRI treatment. Another strategy to assess serotonergic vulnerability has been used in studies that measured HPA-axis hormone secretion following the administration of 5-HT precursors, drugs that stimulate 5-HT release or directly activate 5-HT receptors (Maes and Meltzer, 1995). In particular, 5-HT1A, 5-HT2A and 5-HT2C receptors stimulate cortisol and prolactin secretion in man. In patients with MDD, blunted prolactin responses appear to support evidence for decreased function of 5-HT1A receptors and enhanced cortisol responses for enhanced function of 5-HT2A and 5-HT2C receptors. Patients with MDD have been studied at autopsy using histological methods to measure changes in brain 5-HT receptors. Reliable assessment of neurochemicals after autopsy is subject to variability from the use of different laboratory techniques, the post-mortem interval, heterogeneity of diagnoses and the uncontrolled use of accompanying medications. A reduction of serotonin transporter sites has been reported in the prefrontal cortex of depressed patients, possibly representing widespread impairment of serotonergic function (Arango et al., 2002). This finding may be accompanied by decreased 5-HT1A and increased

5-HT2A receptor binding sites found in deceased depressed patients (Stockmeier, 2003). Although lacking the resolution of histology, imaging studies using positron emission tomography can be used to measure serotonergic targets in MDD (Stout et al., 1996; Stockmeier, 2003; Meyer, 2007). These studies can also control patient selection and medication status. Binding potential for 5-HT transporters has been reported to be elevated in MDD (Cannon et al., 2007; Meyer, 2007). However, there does not appear to be a longstanding change in 5-HT transporter binding potential in recovered medication-free MDD patients (Bhagwagar et al., 2007), indicating normalization with resolution of MDD. Several studies have reported reduced binding potential for 5-HT1A receptor imaging ligands in depressed patients (Drevets et al., 2007). The detection of similar findings in unmedicated (Hirvonen et al., 2008) and remitted depressed individuals (Bhagwagar et al., 2004) support suggestions that reduced 5-HT1A receptor activity is a trait marker associated with MDD. The binding potential for cortical 5-HT2A receptors was reported decreased (Stockmeier, 2003) or increased in unmedicated depressed patients (Meyer et al., 2003), depending on medication history, and remained elevated in unmedicated recovered patients when compared with controls (Bhagwagar et al., 2006). The family of genes that regulate 5-HT transmission or 5-HT receptors has been reported to be associated with MDD or with the therapeutic effects of SSRIs. Several genes for the 5-HT transporter or 5-HT receptors are distributed widely in more than one form across the human population, and they are associated with variations in 5-HT function. The most widely known polymorphism involves the insertion/deletion of either a 528-base pair sequence (long form) or a 484-base pair sequence (short form) within the promoter region of the 5-HT transporter (Lesch et al., 1996). The long form is associated with greater transcription and function. There are many studies that have examined the occurrence of 5-HT transporter polymorphisms with depression and anxiety (Jans et al., 2007), and the short-allele has been associated with depression, anxiety and aggression (Lesch et al., 1996; Lesch, 2001). The 5-HT1A receptor is a key regulator of 5-HT transmission because the presynaptic 5-HT1A receptor regulates neuronal discharge and negative feedback while the postsynaptic 5-HT1A receptor is located in key limbic regions involved in affective behavior. A common polymorphism in the human 5-HT1A promoter region has been identified and was associated with depression and suicide (Le Francois et al., 2008). A polymorphism was identified in the htph2 gene that regulates the synthesis of serotonin and was associated with depression (Zhang et al., 2005), although this was not replicated in a broader sample of depressed patients (Glatt et al., 2005; Van Den Bogaert

The Role of Serotonin in Depression et al., 2005; Zhou et al., 2005). In addition to providing vulnerability for depression and anxiety disorders, several 5-HT genes have been associated with the therapeutic efficacy of SSRIs. Thus, 5-HT transporter polymorphic variations in alleles for the 5-HT transporter, 5-HT1A receptor and 5-HT2A receptors have been associated with rates of recovery for SSRIs in treating depression in some studies (Serretti and Artioli, 2004; McMahon et al., 2006; Lekman et al., 2008; Lin and Chen, 2008). Thus, the family of genes related to 5-HT transmission may serve either as endogenous markers of vulnerability for depression and anxiety or as pharmacogenetic indicators of therapeutic efficacy. It is unlikely that any one patient would show dysfunction of all of the components of 5-HT transmission reported to be altered in MDD. Rather, a general serotonin vulnerability has been proposed as a major risk factor in MDD. Thus, patients may be vulnerable for developing MDD from a composite of individual risk factors associated with the many functional components of 5-HT transmission (Jans et al., 2006). Similarly, therapeutic effectiveness may rely on a composite of 5-HT receptors distributed throughout the brain, rather than on the activity of a single 5-HT receptor in a single locus. The evidence indicates that more than a single type of 5-HT receptor is likely to be involved in producing the behavioral effects of SSRIs.

Behavioral pharmacology of antidepressant drugs This section will focus on behavioral pharmacology studies in rodents that have helped to determine the role of components of the 5-HT system that are involved in treating depression. First, animal models and tests of depression and antidepressant activity that have been used to identify the neurobiological effects of clinically effective antidepressants will be reviewed. Second, the roles of serotonergic mechanisms, including the activation or blockade of individual 5-HT receptors, will be summarized in relation to the animal behavior tests. Over the years, a number of ligands for 5-HT receptors, both agonists and antagonists, have been developed as pharmacological tools in order to delineate the respective contributions of the receptor subtypes. Also, the incorporation of knockout (KO) mice into behavioral pharmacology has generated a wealth of insight into the roles of individual receptors in a number of different behaviors. To this end, numerous 5-HT receptor KO mice have been used to investigate the etiology of depression-like behavior. These studies will also be covered in this section. For a comprehensive review of 5-HT receptors and signaling mechanisms, see Barnes and Sharp (1999).

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Animal tests and models of depression This section will divide animal tests into two types, based on the time-course for the effects of antidepressant compounds in the respective tests and models. First, behavioral tests in which an antidepressant-like effect is evident after a single or small number of administrations will be discussed. The second part will discuss the tests and models that require chronic treatment (⬎2 weeks) with antidepressants in order to display efficacy.

Acute tests Forced swim test (FST) The FST was developed by Porsolt and colleagues as a way to measure the effects of antidepressant compounds in rats and mice (Porsolt et al., 1977). The test involves placing the rodent in a container of water (usually cylindrical) from which the subject is unable to escape. After a period of time in which the subject attempts to escape from the container, the subject adopts a posture of immobility. Immobility is characterized by the lack of movement except that which is necessary to keep the subject’s nose above the water level. In rats, the test consists of two swim exposures. The first is a 15-minute exposure. The second, conducted 24 hours later, is a 5-minute exposure. Immobility time is recorded during the second 5-minute test. In mice, the procedure consists of a single 6-minute test (Porsolt et al., 1978). In the FST, antidepressants cause a decrease in immobility time at doses that do not increase general locomotor activity, unlike psychomotor stimulants (e.g., amphetamine, cocaine), which decrease immobility at doses that increase general locomotor activity. Motivated by the inability of this test to measure the effects of SSRIs, changes in the procedure and scoring of the FST were introduced by Lucki and colleagues as the modified rat FST (Detke et al., 1995a). This version of the FST introduced a set of changes that served to increase the utility of the test. The most important modifications were the switch to identification of component active behaviors along with immobility, the original FST scored only the total duration of immobile time. In the modified rat FST, the frequency of immobility, swimming and climbing is measured over the 5-minute test (Detke et al., 1995a). Swimming is defined as horizontal movement throughout the chamber, and climbing is defined as vertical movement of the forepaws directed towards the sides of the chamber. Serotonergic antidepressants, including SSRIs, selectively increase swimming behavior. This effect was difficult to measure under the test conditions usually used for the original version of the FST.

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In addition, the modified rat FST is able to differentiate between antidepressants that work through serotonergic mechanisms or noradrenergic mechanisms, as noradrenergic compounds selectively increase climbing behavior compared to the increase in swimming behavior seen with serotonergic compounds. Many laboratories have now adopted this scoring system (Cryan et al., 2005). Tail suspension test (TST) The TST is a test of antidepressant activity in mice that shares its experimental rationale with the FST (Steru et al., 1985). In the test, mice are suspended from a lever by their tails and their behavior is recorded over a 6-minute time period. As in the FST, mice struggle to escape for a period of time and then adopt a posture of immobility. The time spent immobile is the dependent measure. As in the FST, antidepressants decrease the amount of time spent immobile without increasing general locomotor activity. Learned helplessness (LH) LH is characterized by the inability of a subject to terminate a controllable stressor by performing a behavior after having been exposed to an uncontrollable stressor (usually foot-shock) (Seligman et al., 1975). LH is thought to simulate many of the symptoms of depression (Seligman et al., 1975). Treatment with antidepressants decreases the escape latency and escape failures in the test after exposure to LH (Leshner et al., 1979; Sherman and Petty, 1980).

Chronic tests and models The next set of tests and models requires chronic treatment with antidepressants in order to induce a change in behavior. These tests are of particular interest to researchers because SSRIs usually require chronic treatment before they produce their clinical effects in depression or anxiety disorders. Novelty suppression of feeding (NSF)/Novelty-induced hypophagia (NIH) The NSF and NIH tests are unique among anxiety tests in that they respond to treatment with antidepressants (Bodnoff et al., 1988; Dulawa et al., 2004). This fact makes them extremely valuable tools in drug discovery, because antidepressants are effective against, and widely prescribed for, anxiety disorders. Both the NSF and NIH tests are conflict-based anxiety tests. They take advantage of rodent species’ natural aversion to bright, open spaces. The measures of anxiety in these tests are the latency to consume food and the amount of food consumed in the novel arena. The differences

between the two tests are that the NSF test uses standard chow and food deprivation in order to drive consumption in the novel arena, and the NIH test uses palatable foods (sweetened) consumed without food deprivation (Dulawa and Hen, 2005). This modification in the NIH procedure removes potential confounds caused by deprivation stress. Consumption in the novel arena is compared to the consumption levels in the home cage. The novel arena is brightly lit, and structurally different from the subject’s home cage. Untreated subjects demonstrate a dramatic decrease in consumption in the novel arena compared to their home-cage consumption. Anxiolytics, such as benzodiazepines, decrease novel arena latency and increase novel arena food consumption without altering home-cage behavior. Antidepressant drugs, when administered chronically, are also able to produce an anxiolytic effect in these tests.

Chronic mild stress (CMS) The rationale for the CMS model is that increased exposure to stressors, particularly unpredictable and uncontrollable stressors, increases the likelihood that a person will develop depression. In order to reproduce this in the laboratory, researchers typically use a set of mild stressors (e.g., strobe lighting, soiled cages, 24-hour lighting) administered in a semi-random fashion in order to mimic the stress of everyday life (Willner, 1997, 2005). A number of groups have been able to show that when administered over a period of weeks, the CMS procedures can lead to behavioral and endocrine changes that appear to be similar to human depression. The most common behavioral output measured during CMS experiments is the presence of anhedonia, represented as a decrease in consumption of a sucrose solution. However, changes in FST behavior, sleep alterations and locomotor activity suggest that the pathological changes resulting from CMS are more comprehensive than just alterations in a single endophenotype (Willner, 2005). The alterations caused by CMS can be reversed by chronic treatment with a number of antidepressant drugs. Another feature that makes CMS an intriguing model is the fact that not all subjects exposed to CMS show a pathological change in behavior, and not all CMS-responsive subjects show a reversal after treatment with antidepressants (Jayatissa et al., 2006). These features are present in human depression, and provide opportunities for research into the neural underpinnings of stress and treatment resistance. A major hindrance to the universal application of CMS in depression research is the difficulty with interlab reproducibility. A number of labs have been successful in the utilization of CMS, but many others have had difficulty implementing the procedure. This may be due to the lack of a standardized stress protocol, but it may also

The Role of Serotonin in Depression be due to unavoidable differences in animal husbandry (e.g., colony room space/size, ventilation) and other issues between institutions (Cryan and Slattery, 2007). Olfactory bulbectomy (OB) Bilateral removal of the olfactory bulbs causes severe behavioral and endocrine changes in rodents (Song and Leonard, 2005). The most common behavioral change monitored in the OB model is hyperactivity in an openfield apparatus. These changes can be reversed by chronic antidepressant drug treatments. These pathological changes are not due purely to the anosmia caused by removal of the olfactory bulbs, since peripheral blockade does not result in an analogous syndrome. There are morphological changes to areas of the limbic system, such as the piriform cortex, that may underlie the effects of the OB procedure (Jarosik et al., 2007).

5-HT system and antidepressant responses The current frontline treatments for depression in humans are the SSRIs. Consequently, these compounds have been tested extensively in rodents. This section will review not the vast number of studies utilizing these compounds alone, but rather the studies that attempt to identify the underlying components of the antidepressant response elicited by the SSRIs. The effects of 5-HT depletion on subsequent treatment effects, the role of individual 5-HT receptors and recent studies of rodents with targeted genetic mutations will be considered. These studies are summarized in Table 1.

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but incomplete depletion of 5-HT, also demonstrated increased TST immobility, but only after repeated testing. Although FST immobility was increased in both sets of mice, this was caused by their inability to swim. A TPH2 knock-in mouse line with reduced TPH2 activity and an 80 percent reduction in brain 5-HT was also reported to have significantly increased immobility times in the TST (Beaulieu et al., 2008). The presence of a depressive behavioral phenotype in the genetic models may be due to the role of 5-HT in development. Considering the accumulating evidence for associating 5-HT insufficiency with vulnerability to depression in humans, these latter genetic preparations provide the first evidence in animals for a pathological role of 5-HT depletion in depressive behavior. Depletion of 5-HT with pCPA blocks the effects of fluoxetine in the FST and the TST, while the effects of desipramine are unaffected by 5-HT depletion (Cesana et al., 1993; Page et al., 1999; Gavioli et al., 2004; O’Leary et al., 2007). These effects demonstrate that serotonergic mechanisms underlie the acute behavioral effects of SSRIs on tests of depressive behavior. These effects in rodents correspond with a similar pattern of relapse induction in clinical patients following the depletion of serotonin or catecholamines. Patients treated with SSRIs will relapse temporarily if 5-HT is depleted by restricting 5-HT synthesis, but not by catecholamine depletion; patients treated with tricyclics demonstrate the complementary pattern of response to relapse induction (Delgado et al., 1991; Delgado, 2004). These studies affirm the importance of changes in 5-HT neurotransmission in contributing to the effects of antidepressant treatments.

5-HT1A receptor 5-HT depletion Pharmacological depletion of 5-HT, by administration of the tryptophan hydroxylase (TPH) inhibitor parachlorophenylalanine (pCPA), does not produce effects on baseline behavior of antidepressant tests in rats or mice (Page et al., 1999; Gavioli et al., 2004; O’Leary et al., 2007). pCPA did increase immobility of female 5-HT1B knockout mice because of their high baseline levels of extracellular 5-HT (Jones and Lucki, 2005a). Mice generated with genetic deletion of the isoforms of TPH, either the major isoform in brain (TPH2) or a double knockout of both isoforms (TPH1 and TPH2), have been examined in tests for depression-related behavior (Savelieva et al., 2008). Mice with complete deletion of TPH (TPH1 and TPH2) showed complete depletion of brain 5-HT from deletion of both TPH isoforms, and were significantly more immobile in the TST. TPH2 KO mice, with a substantial

There is a large body of evidence that 5-HT1A receptor agonists produce antidepressant-like effects (Table 1) across a number of different tests in animals (De Vry, 1995; Blier and Ward, 2003). A number of 5-HT1A agonists decrease immobility in the rat FST (Kostowski et al., 1992; Singh and Lucki, 1993; Lucki et al., 1994). Also, the effects of 5-HT1A agonists, along with the effects of the antidepressants buspirone and desipramine, in the FST are blocked by pretreatment with 5-HT1A antagonists (Detke et al., 1995b). The agonist MKC-242 produces antidepressant (AD)-like effects in the mouse FST even when 5-HT-producing neurons are destroyed or 5-HT synthesis is inhibited. This suggests that the ADlike effects of 5-HT1A receptor agonists are due to activation of postsynaptic 5-HT1A receptors (Matsuda et al., 1995). These effects are not confined to the FST. Alnespirone and VN2222, a 5-HT1A agonist and a mixed

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Table 1 5-HT receptors and rodent behavioral tests of depression Receptor

KO

Agonist

Antagonist

References

5-HT1A

AD-like

AD-like

AD-like

Prodepressive

AD-like

Kowtowski et al., 1992 MacSweeney et al., 1998 Tordera et al., 2000 Cryan et al., 1997 Przegalinski et al., 1995 Hogg and Dalvi, 2004 Jones and Lucki, 2005 Parks et al., 1998 Heisler et al., 1998 Mayorga et al., 2001 Cervo et al., 1989 Dawson et al., 2006 Hogg and Dalvi, 2004 Mayorga et al., 2001 Jones and Lucki, 2005 Albinsson et al., 1994 Patel et al., 2004 Marek et al., 2005 Cryan and Lucki, 2000 Rosenzweig-Lipson et al., 2007 Martin et al., 1992 Bhatnagar et al., 2004 Bravo and Maswood, 2006 Lucas et al., 2007 Svenningsson et al., 2007 Wesolowska and Nikiforuk, 2007 Wesolowska et al., 2007 Guscott et al., 2005 Hedlund et al., 2005 Wesolowska et al., 2006 Holmes et al., 2002 Lira et al., 2003

Augments SSRIs

5-HT1B

AD-like (females) Augments FLX

5-HT2A

No report

5-HT2C

No report

5-HT3

Prodepressive (females)

5-HT4 5-HT6

No report No report

5-HT7

AD-like

SERT

No effect (C57BL6) Mixed effect (129S6) Blocked effects of DMI

AD-like Augments FLX AD-like

AD-like

AD-like AD-like

reuptake inhibitor and 5-HT1A agonist respectively, have been shown to produce AD-like effects in the LH paradigm (MacSweeney et al., 1998; Tordera et al., 2002). Flesinoxan produced AD-like effects in the OB model (Cryan et al., 1997). Also, chronic treatment with the partial agonist buspirone produced AD-like effects in the CMS paradigm (Przegalinski et al., 1995). The 5-HT1A receptor agonist 8-OH-DPAT also increases neurogenesis and survival of new neurons in the dentate gyrus after chronic treatment (Banasr et al., 2004), effects produced by other clinically active ADs. Nevertheless, with the

AD-like

AD-like Augments citalopram

exception of buspirone and gepirone, the development of 5-HT1A receptor agonists as antidepressants has not been clinically successful (Blier and Ward, 2003). Clinically active AD treatments modify the response of 5-HT1A receptors in a number of brain regions. It has been postulated that desensitization of 5-HT1A autoreceptors after chronic treatment with antidepressant drugs is a key factor in antidepressant efficacy, and can account for the delay between the commencement of treatment and the alleviation of depressive symptoms (Piñeyro and Blier, 1999). In contrast, chronic administration of

The Role of Serotonin in Depression antidepressant treatments facilitates transmission mediated by 5-HT1A receptors in postsynaptic regions, like the hippocampus (Burnet et al., 1995; Haddjeri et al., 1998; Shen et al., 2002). Because antagonism of 5-HT1A autoreceptors in the raphe nuclei could facilitate AD-like effects through disinhibition of 5-HT release, 5-HT1A receptor antagonists were proposed as a promising adjunct to traditional AD treatment (Artigas et al., 1996). 5-HT1A KO mice have been generated and studied by multiple labs (Heisler et al., 1998; Parks et al., 1998). Loss of the 5-HT1A receptor results in an antidepressantlike and anxiogenic phenotype (Heisler et al., 1998; Parks et al., 1998; Zhuang et al., 1999; Jones and Lucki, 2005b). This lifelong phenotype is caused by the loss of the 5-HT1A receptor during early development in the rodent (Gross et al., 2002). Although 5-HT1A KO mice exhibit normal basal and K⫹-evoked release of 5-HT, the absence of 5-HT1A autoreceptors causes an exaggerated increase of 5-HT levels in response to fluoxetine (Knobelman et al., 2001). Nevertheless, 5-HT1A KO mice demonstrate refractory behavioral responses to acute or chronic SSRI treatment, probably because of the absence of postsynaptic 5-HT1A receptors (Mayorga et al., 2001; Santarelli et al., 2003). A polymorphic allele in the 5-HT1A receptor promoter region in humans has been identified as a risk allele for depression and anxiety disorders, and resistance to the effects of SSRIs (Le Francois et al., 2008).

5-HT1B receptor The 5-HT1B receptor is regulated by exposure to behavioral tests for antidepressants and following chronic antidepressant treatments. The stress of the LH procedure causes an up-regulation of the 5-HT1B receptor in the cortex, hippocampus, septum and dorsal raphe (Edwards et al., 1991; Neumaier et al., 1997). Chronic AD treatment decreases the mRNA of the 5-HT1B receptor in the dorsal raphe and decreases the efficacy of 5-HT1B autoreceptors, which may lead to an increase in 5-HT release (Neumaier et al., 1996; Piñeyro and Blier, 1999; Anthony and Sexton, 2000; Gur et al., 2000). 5-HT1B heteroreceptors in the dentate gyrus appear to contribute to increases of neurogenesis, a marker of AD treatment (Banasr et al., 2004). Also, up-regulation of p11, a protein that increases 5-HT1B receptor function in a number of brain regions, reduces depression-like symptoms (Svenningsson et al., 2006). The actions of ligands at the 5-HT1B receptor produce results that correspond with the changes in the receptor seen after stress and AD treatment (Table 1). The agonist TFMPP, given systemically and locally within the ventral tegmental area (VTA), blocks the effects of desipramine in the rat FST (Cervo et al., 1989).

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5-HT1B receptor antagonists have been shown to produce AD-like effects and augment the effects of traditional ADs in the FST (Hogg and Dalvi, 2004; Tatarczynska et al., 2004; Dawson et al., 2006). A 5-HT1B receptor knockout mouse has been generated that demonstrates increased aggression and reduced anxiety (Zhuang et al., 1999). Although male 5-HT1B KO male mice do not exhibit an AD-like baseline response in the TST, they do show exaggerated increases of 5-HT and augmented behavioral responses to fluoxetine (Knobelman et al., 2001; Mayorga et al., 2001), suggesting an important role for 5-HT1B autoreceptors. 5-HT1B KO females exhibit a decrease in baseline immobility in the TST and FST compared to KO males and WT mice because of a constitutive disinhibition of 5-HT release (Jones and Lucki, 2005b).

5-HT2A receptor Much of the research on 5-HT2A receptors has focused on their role in the modulation of dopamine and glutamate release in the medial prefrontal cortex. Antagonists at the receptor have been shown to inhibit dopamine release in the prefrontal cortex (Pehek et al., 2006). Treatment with the 5-HT2A/2C receptor agonist DOI causes an increase in glutamate release in the cortex that is blocked by pretreatment with a selective 5-HT2A receptor antagonist (Scruggs et al., 2003). Selective 5-HT2A receptor antagonists may cause AD-like effects (Table 1) in a number of rodent tests (Albinsson et al., 1994; Patel et al., 2004), and co-administration of 5-HT2A receptor antagonists can augment the antidepressant-like effects of SSRIs (Marek et al., 2003, 2005).

5-HT2c receptor Treatment with 5-HT2C receptor agonists produces ADlike effects (Table 1) in the modified rat FST, resident– intruder social stress model, and OB models of depression (Cryan and Lucki, 2000; Rosenzweig-Lipson et al., 2007). In addition, the selective 5-HT2C receptor antagonist SB206533 blocks the behavioral effects of fluoxetine (Cryan and Lucki, 2000). Although the antidepressant mianserin is a 5-HT2C receptor antagonist, it produces antidepressant-like effects by blocking α2 noradrenergic receptors (Cryan and Lucki, 2000). In the mouse FST, the 5-HT2C receptor agonist Ro 60-0175 synergized with subactive doses of imipramine, paroxetine, citalopram and fluvoxamine, but antagonized active doses of paroxetine and fluoxetine at higher doses (Clenet et al., 2001). 5-HT2C KO mice demonstrate an anxiolytic phenotype with a blunted

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CRF response to stress, but their phenotype in depression tests was not reported (Heisler et al., 2007). That 5-HT2C KO mice are hyper-responsive to the effects of repeated stress would seem to support the findings that agonists can produce AD-like effects (Chou-Green et al., 2003). On the other hand, some 5-HT2C receptor antagonists, including the combined melatonin agonist/5-HT2C antagonist agomelatine, have been reported to produce antidepressantlike effects (Bourin et al., 2004; Dekeyne et al., 2008).

5-HT3 receptor Antagonists at the 5-HT3 receptor produce antidepressant-like effects (Table 1) in a number of tests and models (Martin et al., 1992; Mahesh et al., 2007) and cotreatment can augment the effects of sub-threshold doses of SSRIs (Redrobe and Bourin, 1997; Ramamoorthy et al., 2008). On the other hand, 5-HT3 receptor agonists were shown to attenuate the effects of antidepressant compounds in the rat FST (Nakagawa et al., 1998). The effects of 5-HT3 receptor antagonists may be due to a direct receptor interaction, because some clinically effective antidepressants have been reported to be functional antagonists at the 5-HT3 receptor (Eisensamer et al., 2003). Interestingly, female 5-HT3 receptor KO mice show increased immobility in the FST compared to WT controls, suggesting that there is sex-specific regulation of the receptor (Martin et al., 1992; Bhatnagar et al., 2004; Bravo and Maswood, 2006).

5-HT4 receptor 5-HT4 receptor agonists exhibit antidepressant-like effects (Table 1) in rats in a number of tests (FST, OB, and CMS). Most interestingly, 5-HT4 receptor agonists produce a rapid onset of a number of adaptations seen after chronic AD treatment. Only a 3-day treatment regimen was required to desensitize 5-HT1 autoreceptors, increase hippocampal neurogenesis, decrease hyperlocomotion in the OB model, and normalize sucrose consumption in the CMS model (Lucas et al., 2007). Pharmacological blockade or genetic deletion of the 5-HT4 receptor appears to exert anxiolytic effects (Smriga and Torii, 2003; Compan et al., 2004; Conductier et al., 2006).

5-HT6 receptor Research has shown that similar effects are seen after treatment with both agonists and antagonists (Table 1). Both sets of compounds produce antidepressant-like

and anxiolytic effects in a number of rodent tests (Svenningsson et al., 2007; Wesolowska and Nikiforuk, 2007; Wesolowska et al., 2007). There is also evidence that the effects of 5-HT6 receptor agonists may involve modulation of GABAergic neurotransmission (Schechter et al., 2008).

5-HT7 receptor Genetic deletion and treatment with 5-HT7 receptor antagonists produce AD-like effects (Table 1) in the FST and TST (Guscott et al., 2005; Hedlund et al., 2005; Wesolowska et al., 2006). Research also suggests that 5-HT7 receptor antagonists have potential as adjunct AD treatments. A recent study showed that 5-HT7 receptor antagonists increased the effects of citalopram on TST (mice) and REM sleep (rats) (Bonaventure et al., 2007).

5-HT transporter (SERT) KO mice The depression-related behavior of SERT KO mice appears to be affected by the background strain used to create the mouse. With a C57/BL6 background, there are no differences in baseline behavior (Table 1) in the FST or TST between KO and wild-type (WT) mice (Holmes et al., 2002). However, on the 129S6 background, SERT KO mice exhibit an increase in immobility in the FST (pro-depressive) and a decrease in immobility in the TST (AD-like) response at baseline compared to WT controls (Holmes et al., 2002; Lira et al., 2003). On the C57/BL6 background, fluoxetine has no effect on behavior in the TST, while antidepressants that are not dependent on 5-HT to exert their effects (desipramine and imipramine) are still effective (Holmes et al., 2002). It is unclear why deletion of the SERT protein does not produce the same behavioral effects as pharmacological blockade of the protein with SSRIs, but possible explanations include the developmental alteration of 5-HT receptor function and/or changes in the endogenous release of 5-HT (Fabre et al., 2000; Gobbi et al., 2001).

Conclusion A large amount of research has elucidated the role of the 5-HT system in genetic and molecular mechanisms underlying the pathology and treatment of depression. Instead of focusing on one component of 5-HT transmission as the source for depression vulnerability, the current concept identifies different 5-HT genes and pathways as a family of risk factors that can contribute to the pathology

The Role of Serotonin in Depression of depression (Jans et al., 2007). The genetic models of the deletion of TPH and 5-HT receptors emphasizes the critical role of 5-HT during development for the lifelong expression of normal affective behaviors. Although genetic deletion of individual 5-HT receptors has not yet reliably reproduced a depressive behavioral phenotype, the genetic deletion of TPH may reproduce a depressivelike behavioral phenotype. Behavioral and neuropharmacology studies have attempted to identify the 5-HT receptors associated with the therapeutic effects of SSRIs. Identifying the 5-HT receptors that support the therapeutic effects of SSRIs may lead to the development of more effective antidepressant drugs with fewer side effects. However, the present findings indicate that multiple 5-HT receptors are likely to participate in antidepressant responses, and it is unclear that the entire antidepressant effect of SSRIs can be recapitulated by a selective 5-HT receptor agonist or antagonist. However, many of the 5-HT receptors have been discovered only recently. Therefore, selective agonists and antagonists have not yet been synthesized, and specific investigation of the effects mediated by these receptors has not been fully possible. Undoubtedly, behavioral testing in animals, particularly utilizing the models outlined in this chapter, will play an important role in the further exploration of the relationship between the 5-HT system and depression.

References Albinsson, A., Bjork, A., Svartengren, J., Klint, T. and Andersson, G. (1994) Preclinical pharmacology of FG5893: a potential anxiolytic drug with high affinity for both 5-HT1A and 5-HT2A receptors. Eur. J. Pharmacol., 261: 285–294. Anthony, J.P., Sexton, T.J. and Neumaier, J.F. (2000) Antidepressant-induced regulation of 5-HT(1b) mRNA in rat dorsal raphe nucleus reverses rapidly after drug discontinuation. J. Neurosci. Res., 61: 82–87. Arango, V., Underwood, M.D. and Mann, J.J. (2002) Serotonin brain circuits involved in major depression and suicide. Prog. Brain Res., 136: 443–453. Artigas, F., Romero, L., de Montigny, C. and Blier, P. (1996) Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Trends Neurosci., 19: 378–383. Asberg, M. (1997) Neurotransmitters and suicidal behavior. The evidence from cerebrospinal fluid studies. Ann. N. Y. Acad. Sci., 836: 158–181. Banasr, M., Hery, M., Printemps, R. and Daszuta, A. (2004) Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology, 29: 450–460. Barnes, N.M. and Sharp, T. (1999) A review of central 5HT receptors and their function. Neuropharmacology, 38: 1083–1152.

501

Beaulieu, J.M., Zhang, X., Rodriguiz, R.M., Sotnikova, T.D., Cools, M.J., Wetsel, W.C., Gainetdinov, R.R. and Caron, M. G. (2008) Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency. Proc. Natl. Acad. Sci. USA, 105: 1333–1338. Bhagwagar, Z., Rabiner, E.A., Sargent, P.A., Grasby, P.M. and Cowen, P.J. (2004) Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635. Mol. Psychiatry, 9: 386–392. Bhagwagar, Z., Hinz, R., Taylor, M., Fancy, S., Cowen, P. and Grasby, P. (2006) Increased 5-HT(2A) receptor binding in euthymic, medication-free patients recovered from depression: a positron emission study with [(11)C]MDL 100,907. Am. J. Psychiatry, 163: 1580–1587. Bhagwagar, Z., Murthy, N., Selvaraj, S., Hinz, R., Taylor, M., Fancy, S., Grasby, P. and Cowen, P. (2007) 5-HTT binding in recovered depressed patients and healthy volunteers: a positron emission tomography study with [11C]DASB. Am. J. Psychiatry, 164: 1858–1865. Bhatnagar, S., Nowak, N., Babich, L. and Bok, L. (2004) Deletion of the 5-HT3 receptor differentially affects behavior of males and females in the Porsolt forced swim and defensive withdrawal tests. Behav. Brain Res., 153: 527–535. Blier, P. and Ward, N.M. (2003) Is there a role for 5-HT1A agonists in the treatment of depression? Biol. Psychiatry, 53: 193–203. Bodnoff, S.R., Suranyi-Cadotte, B., Aitken, D.H., Quirion, R. and Meaney, M.J. (1988) The effects of chronic antidepressant treatment in an animal model of anxiety. Psychopharmacology (Berl.), 95: 298–302. Bonaventure, P., Kelly, L., Aluisio, L., Shelton, J., Lord, B., Galici, R., Miller, K., Atack, J., Lovenberg, T.W. and Dugovic, C. (2007) Selective blockade of 5-hydroxytryptamine (5-HT)7 receptors enhances 5-HT transmission, antidepressant-like behavior, and rapid eye movement sleep suppression induced by citalopram in rodents. J. Pharmacol. Exp. Ther., 321: 690–698. Bourin, M., Mocaer, E. and Porsolt, R. (2004) Antidepressantlike activity of S 20098 (agomelatine) in the forced swimming test in rodents: involvement of melatonin and serotonin receptors. J. Psychiatry Neurosci., 29: 126–133. Bravo, G. and Maswood, S. (2006) Acute treatment with 5HT3 receptor antagonist, tropisetron, reduces immobility in intact female rats exposed to the forced swim test. Pharmacol. Biochem. Behav., 85: 362–368. Burnet, P.W., Mead, A., Eastwood, S.L., Lacey, K., Harrison, P.J. and Sharp, T. (1995) Repeated ECS differentially affects rat brain 5-HT1A and 5-HT2A receptor expression. Neuroreport, 6: 901–904. Cannon, D.M., Ichise, M., Rollis, D., Klaver, J.M., Gandhi, S.K., Charney, D.S., Manji, H.K. and Drevets, W.C. (2007) Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [11C]DASB; comparison with bipolar disorder. Biol. Psychiatry, 62: 870–877. Cervo, L., Grignaschi, G., Nowakowska, E. and Samanin, R. (1989) 1-(3-Trifluoromethylphenyl) piperazine (TFMPP) in the ventral tegmental area reduces the effect of desipramine in the forced swimming test in rats: possible role of serotonin receptors. Eur. J. Pharmacol., 171: 119–125. Cesana, R., Ceci, A., Ciprandi, C. and Borsini, F. (1993) Mesulergine antagonism towards the fluoxetine anti-immobility

502

Serotonin in Disease Conditions

effect in the forced swimming test in mice. J. Pharm. Pharmacol., 45: 473–475. Chou-Green, J.M., Holscher, T.D., Dallman, M.F. and Akana, S.F. (2003) Repeated stress in young and old 5-HT(2C) receptor knockout mice. Physiol. Behav., 79: 217–226. Clenet, F., De Vos, A. and Bourin, M. (2001) Involvement of 5-HT(2C) receptors in the anti-immobility effects of antidepressants in the forced swimming test in mice. Eur. Neuropsychopharmacol., 11: 145–152. Compan, V., Zhou, M., Grailhe, R., Gazzara, R.A., Martin, R., Gingrich, J., Dumuis, A., Brunner, D., Bockaert, J. and Hen, R. (2004) Attenuated response to stress and novelty and hypersensitivity to seizures in 5-HT4 receptor knockout mice. J. Neurosci., 24: 412–419. Conductier, G., Dusticier, N., Lucas, G., Cote, F., Debonnel, G., Daszuta, A., Dumuis, A., Nieoullon, A., Hen, R., Bockaert, J. and Compan, V. (2006) Adaptive changes in serotonin neurons of the raphe nuclei in 5-HT(4) receptor knockout mouse. Eur. J. Neurosci., 24: 1053–1062. Cowen, P.J., Parry-Billings, M. and Newsholme, E.A. (1989) Decreased plasma tryptophan levels in major depression. J. Affect. Disord., 16: 27–31. Cryan, J.F. and Lucki, I. (2000) Antidepressant-like behavioral effects mediated by 5-Hydroxytryptamine(2C) receptors. J. Pharmacol. Exp. Ther., 295: 1120–1126. Cryan, J.F. and Slattery, D.A. (2007) Animal models of mood disorders: recent developments. Curr. Opin. Psychiatry, 20: 1–7. Cryan, J.F., Redmond, A.M., Kelly, J.P. and Leonard, B.E. (1997) The effects of the 5-HT1A agonist flesinoxan, in three paradigms for assessing antidepressant potential in the rat. Eur. Neuropsychopharmacol., 7: 109–114. Cryan, J.F., Valentino, R.J. and Lucki, I. (2005) Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci. Biobehav. Rev., 29: 547–569. Dawson, L.A., Hughes, Z.A., Starr, K.R., Storey, J.D., Bettelini, L., Bacchi, F., Arban, R., Poffe, A., Melotto, S., Hagan, J.J. and Price, G.W. (2006) Characterisation of the selective 5-HT1B receptor antagonist SB-616234-A (1-[6-(cis-3,5-dimethylpiperazin-1-yl)-2,3-dihydro-5-methoxyindol-1-yl]-1- [2’-methyl-4’(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methanone hydrochloride): in vivo neurochemical and behavioural evidence of anxiolytic/antidepressant activity. Neuropharmacology, 50: 975–983. Dekeyne, A., Mannoury la Cour, C., Gobert, A., Brocco, M., Lejeune, F., Serres, F., Sharp, T., Daszuta, A., Soumier, A., Papp, M., Rivet, J.M., Flik, G., Cremers, T.I., Muller, O., Lavielle, G. and Millan, M.J. (2008) S32006, a novel 5-HT2C receptor antagonist displaying broad-based antidepressant and anxiolytic properties in rodent models. Psychopharmacology (Berl.), 199: 549–568. Delgado, P.L. (2004) How antidepressants help depression: mechanisms of action and clinical response. J. Clin. Psychiatry, 65(Suppl 4): 25–30. Delgado, P.L., Price, L.H., Miller, H.L., Salomon, R.M., Licinio, J., Krystal, J.H., Heninger, G.R. and Charney, D.S. (1991) Rapid serotonin depletion as a provocative challenge test for patients with major depression: relevance to antidepressant action and the neurobiology of depression. Psychopharmacol. Bull., 27: 321–330. Delgado, P.L., Miller, H.L., Salomon, R.M., Licinio, J., Krystal, J.H., Moreno, F.A., Heninger, G.R. and Charney, D.S. (1999)

Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. Biol. Psychiatry, 46: 212–220. Detke, M.J., Rickels, M. and Lucki, I. (1995a) Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology (Berl.), 121: 66–72. Detke, M.J., Wieland, S. and Lucki, I. (1995b) Blockade of the antidepressant-like effects of 8-OH-DPAT, buspirone and desipramine in the rat forced swim test by 5HT1A receptor antagonists. Psychopharmacology (Berl.), 119: 47–54. De Vry, J. (1995) 5-HT1A receptor agonists: recent developments and controversial issues. Psychopharmacology (Berl.), 121: 1–26. Drevets, W.C., Thase, M.E., Moses-Kolko, E.L., Price, J., Frank, E., Kupfer, D.J. and Mathis, C. (2007) Serotonin-1A receptor imaging in recurrent depression: replication and literature review. Nucl. Med. Biol., 34: 865–877. Dulawa, S.C., Holick, K.A., Gundersen, B. and Hen, R. (2004) Effects of chronic fluoxetine in animal models of anxiety and depression. Neuropsychopharmacology, 29: 1321–1330. Dulawa, S.C. and Hen, R. (2005) Recent advances in animal models of chronic antidepressant effects: the novelty-induced hypophagia test. Neurosci. Biobehav. Rev., 29: 771–783. Edwards, E., Harkins, K., Wright, G. and Henn, F.A. (1991) 5-HT1b receptors in an animal model of depression. Neuropharmacology, 30: 101–105. Eisensamer, B., Rammes, G., Gimpl, G., Shapa, M., Ferrari, U., Hapfelmeier, G., Bondy, B., Parsons, C., Gilling, K., Zieglgansberger, W., Holsboer, F. and Rupprecht, R. (2003) Antidepressants are functional antagonists at the serotonin type 3 (5–HT3) receptor. Mol. Psychiatry, 8: 994–1007. Fabre, V., Beaufour, C., Evrard, A., Rioux, A., Hanoun, N., Lesch, K.P., Murphy, D.L., Lanfumey, L., Hamon, M. and Martres, M.P. (2000) Altered expression and functions of serotonin 5-HT1A and 5-HT1B receptors in knockout mice lacking the 5-HT transporter. Eur. J. Neurosci., 12: 2299–2310. Gavioli, E.C., Vaughan, C.W., Marzola, G., Guerrini, R., Mitchell, V.A., Zucchini, S., De Lima, T.C., Rae, G.A., Salvadori, S., Regoli, D. and Calo, G. (2004) Antidepressantlike effects of the nociceptin/orphanin FQ receptor antagonist UFP-101: new evidence from rats and mice. Naunyn. Schmiedebergs Arch. Pharmacol., 369: 547–553. Glatt, C.E., Carlson, E., Taylor, T.R., Risch, N., Reus, V.I. and Schaefer, C.A. (2005) Response to Zhang et al. (2005): lossof-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron, 45: 11–16. Neuron 48: 704–705; author reply 705–706. Gobbi, G., Murphy, D.L., Lesch, K. and Blier, P. (2001) Modifications of the serotonergic system in mice lacking serotonin transporters: an in vivo electrophysiological study. J. Pharmacol. Exp. Ther., 296: 987–995. Gross, C., Zhuang, X., Stark, K., Ramboz, S., Oosting, R., Kirby, L., Santarelli, L., Beck, S. and Hen, R. (2002) Serotonin1A receptor acts during development to establish normal anxietylike behaviour in the adult. Nature, 416: 396–400. Gur, E., Lerer, B., Dremencov, E. and Newman, M.E. (2000) Chronic repetitive transcranial magnetic stimulation induces subsensitivity of presynaptic serotonergic autoreceptor activity in rat brain. Neuroreport, 11: 2925–2929. Guscott, M., Bristow, L.J., Hadingham, K., Rosahl, T.W., Beer, M.S., Stanton, J.A., Bromidge, F., Owens, A.P., Huscroft, I.,

The Role of Serotonin in Depression Myers, J., Rupniak, N.M., Patel, S., Whiting, P.J., Hutson, P.H., Fone, K.C., Biello, S.M., Kulagowski, J.J. and McAllister, G. (2005) Genetic knockout and pharmacological blockade studies of the 5-HT7 receptor suggest therapeutic potential in depression. Neuropharmacology, 48: 492–502. Haddjeri, N., Blier, P. and de Montigny, C. (1998) Long-term antidepressant treatments result in a tonic activation of forebrain 5-HT1A receptors. J. Neurosci., 18: 10150–10156. Hedlund, P.B., Huitron-Resendiz, S., Henriksen, S.J. and Sutcliffe, J.G. (2005) 5-HT7 receptor inhibition and inactivation induce antidepressantlike behavior and sleep pattern. Biol. Psychiatry, 58: 831–837. Heisler, L.K., Chu, H.M., Brennan, T.J., Danao, J.A., Bajwa, P., Parsons, L.H. and Tecott, L.H. (1998) Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc. Natl. Acad. Sci. USA, 95: 15049–15054. Heisler, L.K., Zhou, L., Bajwa, P., Hsu, J. and Tecott, L.H. (2007) Serotonin 5-HT(2C) receptors regulate anxiety-like behavior. Genes Brain Behav., 6: 491–496. Hirvonen, J., Karlsson, H., Kajander, J., Lepola, A., Markkula, J., Rasi-Hakala, H., Nagren, K., Salminen, J.K. and Hietala, J. (2008) Decreased brain serotonin 5-HT1A receptor availability in medication-naive patients with major depressive disorder: an in-vivo imaging study using PET and [carbonyl-11C]WAY-100635. Int. J. Neuropsychopharmacol., 11: 465–476. Hogg, S. and Dalvi, A. (2004) Acceleration of onset of action in schedule-induced polydipsia: combinations of SSRI and 5-HT1A and 5-HT1B receptor antagonists. Pharmacol. Biochem. Behav., 77: 69–75. Holmes, A., Yang, R.J., Murphy, D.L. and Crawley, J.N. (2002) Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter. Neuropsychopharmacology, 27: 914–923. Jans, L.A., Riedel, W.J., Markus, C.R. and Blokland, A. (2006) Serotonergic vulnerability and depression: assumptions, experimental evidence and implications. Mol. Psychiatry, 12: 522–543. Jans, L.A., Riedel, W.J., Markus, C.R. and Blokland, A. (2007) Serotonergic vulnerability and depression: assumptions, experimental evidence and implications. Mol. Psychiatry, 12: 522–543. Jarosik, J., Legutko, B., Unsicker, K., von Bohlen, and Und Halbach, O. (2007) Antidepressant-mediated reversal of abnormal behavior and neurodegeneration in mice following olfactory bulbectomy. Exp. Neurol., 204: 20–28. Jayatissa, M.N., Bisgaard, C., Tingstrom, A., Papp, M. and Wiborg, O. (2006) Hippocampal cytogenesis correlates to escitalopram-mediated recovery in a chronic mild stress rat model of depression. Neuropsychopharmacology, 31: 2395–2404. Jones, M.D. and Lucki, I. (2005a) Sex differences in the regulation of serotonergic transmission and behavior in 5-HT receptor knockout mice. Neuropsychopharmacology, 30: 1039–1047. Jones, M.D. and Lucki, I. (2005b) Sex differences in the regulation of serotonergic transmission and behavior in 5-HT receptor knockout mice. Neuropsychopharmacology, 30: 1039–1047. Knobelman, D.A., Hen, R. and Lucki, I. (2001) Genetic regulation of extracellular serotonin by 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) autoreceptors in different brain regions of the mouse. J. Pharmacol. Exp. Ther., 298: 1083–1091.

503

Kostowski, W., Dyr, W., Krzascik, P., Jarbe, T. and Archer, T. (1992) 5-Hydroxytryptamine1A receptor agonists in animal models of depression and anxiety. Pharmacol. Toxicol., 71: 24–30. Le Francois, B., Czesak, M., Steubl, D. and Albert, P.R. (2008) Transcriptional regulation at a HTR1A polymorphism associated with mental illness. Neuropharmacology, 55: 977–985. Lekman, M., Paddock, S. and McMahon, F.J. (2008) Pharmacogenetics of major depression: insights from level 1 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Mol. Diagn. Ther., 12: 321–330. Lesch, K.P. (2001) Serotonergic gene expression and depression: implications for developing novel antidepressants. J. Affect. Disord., 62: 57–76. Lesch, K.P., Bengel, D., Heils, A., Sabol, S.Z., Greenberg, B.D., Petri, S., Benjamin, J., Muller, C.R., Hamer, D.H. and Murphy, D.L. (1996) Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science, 274: 1527–1531. Leshner, A.I., Remler, H., Biegon, A. and Samuel, D. (1979) Desmethylimipramine (DMI) counteracts learned helplessness in rats. Psychopharmacology (Berl.), 66: 207–208. Lin, E. and Chen, P.S. (2008) Pharmacogenomics with antidepressants in the STAR*D study. Pharmacogenomics, 9: 935–946. Lira, A., Zhou, M., Castanon, N., Ansorge, M.S., Gordon, J.A., Francis, J.H., Bradley-Moore, M., Lira, J., Underwood, M.D., Arango, V., Kung, H.F., Hofer, M.A., Hen, R. and Gingrich, J.A. (2003) Altered depression-related behaviors and functional changes in the dorsal raphe nucleus of serotonin transporterdeficient mice. Biol. Psychiatry, 54: 960–971. Lucas, G., Rymar, V.V., Du, J., Mnie-Filali, O., Bisgaard, C., Manta, S., Lambas-Senas, L., Wiborg, O., Haddjeri, N., Piñeyro, G., Sadikot, A.F. and Debonnel, G. (2007) Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action. Neuron, 55: 712–725. Lucki, I., Singh, A. and Kreiss, D.S. (1994) Antidepressant-like behavioral effects of serotonin receptor agonists. Neurosci. Biobehav. Rev., 18: 85–95. MacSweeney, C.P., Lesourd, M. and Gandon, J.M. (1998) Antidepressant-like effects of alnespirone (S 20499) in the learned helplessness test in rats. Eur. J. Pharmacol., 345: 133–137. Maes, M. and Meltzer, H.Y. (1995) The Serotonin Hypothesis of Major Depression. Raven Press, New York. Maes, M., Jacobs, M.P., Suy, E., Minner, B., Leclercq, C., Christiaens, F. and Raus, J. (1990) Suppressant effects of dexamethasone on the availability of plasma L-tryptophan and tyrosine in healthy controls and in depressed patients. Acta Psychiatr. Scand., 81: 19–23. Mahesh, R., Rajkumar, R., Minasri, B. and Venkatesha Perumal, R. (2007) Potential antidepressants: pharmacology of 2methyl piperazin-1-yl)-1,8-naphthyridine-3-carbonitrile in rodent behavioural models. Pharmazie, 62: 919–924. Marek, G.J., Carpenter, L.L., McDougle, C.J. and Price, L.H. (2003) Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology, 28: 402–412. Marek, G.J., Martin-Ruiz, R., Abo, A. and Artigas, F. (2005) The selective 5-HT2A receptor antagonist M100907 enhances antidepressant-like behavioral effects of the SSRI fluoxetine. Neuropsychopharmacology, 30: 2205–2215.

504

Serotonin in Disease Conditions

Martin, P., Gozlan, H. and Puech, A.J. (1992) 5-HT3 receptor antagonists reverse helpless behaviour in rats. Eur. J. Pharmacol., 212: 73–78. Matsuda, T., Somboonthum, P., Suzuki, M., Asano, S. and Baba, A. (1995) Antidepressant-like effect by postsynaptic 5-HT1A receptor activation in mice. Eur. J. Pharmacol., 280: 235–238. Mayorga, A.J., Dalvi, A., Page, M.E., Zimov-Levinson, S., Hen, R. and Lucki, I. (2001) Antidepressant-like behavioral effects in 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) receptor mutant mice. J. Pharmacol. Exp. Ther., 298: 1101–1107. McMahon, F.J., Buervenich, S., Charney, D., Lipsky, R., Rush, A.J., Wilson, A.F., Sorant, A.J., Papanicolaou, G.J., Laje, G., Fava, M., Trivedi, M.H., Wisniewski, S.R. and Manji, H. (2006) Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am. J. Hum. Genet., 78: 804–814. Meyer, J.H. (2007) Imaging the serotonin transporter during major depressive disorder and antidepressant treatment. J. Psychiatry Neurosci., 32: 86–102. Meyer, J.H., McMain, S., Kennedy, S.H., Korman, L., Brown, G.M., DaSilva, J.N., Wilson, A.A., Blak, T., Eynan-Harvey, R., Goulding, V.S., Houle, S. and Links, P. (2003) Dysfunctional attitudes and 5-HT2 receptors during depression and self-harm. Am. J. Psychiatry, 160: 90–99. Moreno, F.A., Gelenberg, A.J., Heninger, G.R., Potter, R.L., McKnight, K.M., Allen, J., Phillips, A.P. and Delgado, P.L. (1999) Tryptophan depletion and depressive vulnerability. Biol. Psychiatry, 46: 498–505. Nakagawa, Y., Ishima, T. and Takashima, T. (1998) The 5-HT3 receptor agonist attenuates the action of antidepressants in the forced swim test in rats. Brain Res., 786: 189–193. Neumaier, J.F., Root, D.C. and Hamblin, M.W. (1996) Chronic fluoxetine reduces serotonin transporter mRNA and 5-HT1B mRNA in a sequential manner in the rat dorsal raphe nucleus. Neuropsychopharmacology, 15: 515–522. Neumaier, J.F., Petty, F., Kramer, G.L., Szot, P. and Hamblin, M.W. (1997) Learned helplessness increases 5hydroxytryptamine1B receptor mRNA levels in the rat dorsal raphe nucleus. Biol. Psychiatry, 41: 668–674. Neumeister, A., Nugent, A.C., Waldeck, T., Geraci, M., Schwarz, M., Bonne, O., Bain, E.E., Luckenbaugh, D.A., Herscovitch, P., Charney, D.S. and Drevets, W.C. (2004) Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls. Arch. Gen. Psychiatry, 61: 765–773. O’Leary, O.F., Bechtholt, A.J., Crowley, J.J., Hill, T.E., Page, M.E. and Lucki, I. (2007) Depletion of serotonin and catecholamines block the acute behavioral response to different classes of antidepressant drugs in the mouse tail suspension test. Psychopharmacology (Berl.), 192: 357–371. Page, M.E., Detke, M.J., Dalvi, A., Kirby, L.G. and Lucki, I. (1999) Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the rat forced swimming test. Psychopharmacology (Berl.), 147: 162–167. Parks, C.L., Robinson, P.S., Sibille, E., Shenk, T. and Toth, M. (1998) Increased anxiety of mice lacking the serotonin1A receptor. Proc. Natl. Acad. Sci. USA, 95: 10734–10739. Patel, J.G., Bartoszyk, G.D., Edwards, E. and Ashby, C.R. Jr. (2004) The highly selective 5-hydroxytryptamine (5-HT)2A receptor antagonist, EMD 281014, significantly increases swimming and decreases immobility in male congenital

learned helpless rats in the forced swim test. Synapse, 52: 73–75. Pehek, E.A., Nocjar, C., Roth, B.L., Byrd, T.A. and Mabrouk, O.S. (2006) Evidence for the preferential involvement of 5-HT2A serotonin receptors in stress- and drug-induced dopamine release in the rat medial prefrontal cortex. Neuropsychopharmacology, 31: 265–277. Piñeyro, G. and Blier, P. (1999) Autoregulation of serotonin neurons: role in antidepressant drug action. Pharmacol. Rev., 51: 533–591. Placidi, G.P., Oquendo, M.A., Malone, K.M., Huang, Y.Y., Ellis, S.P. and Mann, J.J. (2001) Aggressivity, suicide attempts, and depression: relationship to cerebrospinal fluid monoamine metabolite levels. Biol. Psychiatry, 50: 783–791. Porsolt, R.D., Le Pichon, M. and Jalfre, M. (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature, 266: 730–732. Porsolt, R.D., Bertin, A. and Jalfre, M. (1978) ‘Behavioural despair’ in rats and mice: strain differences and the effects of imipramine. Eur. J. Pharmacol., 51: 291–294. Przegalinski, E., Moryl, E. and Papp, M. (1995) The effect of 5-HT1A receptor ligands in a chronic mild stress model of depression. Neuropharmacology, 34: 1305–1310. Ramamoorthy, R., Radhakrishnan, M. and Borah, M. (2008) Antidepressant-like effects of serotonin type-3 antagonist, ondansetron: an investigation in behaviour-based rodent models. Behav. Pharmacol., 19: 29–40. Redrobe, J.P. and Bourin, M. (1997) Partial role of 5-HT2 and 5-HT3 receptors in the activity of antidepressants in the mouse forced swimming test. Eur. J. Pharmacol., 325: 129–135. Rosenzweig-Lipson, S., Sabb, A., Stack, G., Mitchell, P., Lucki, I., Malberg, J.E., Grauer, S., Brennan, J., Cryan, J.F., Sukoff Rizzo, S.J., Dunlop, J., Barrett, J.E. and Marquis, K.L. (2007) Antidepressant-like effects of the novel, selective, 5-HT2C receptor agonist WAY-163909 in rodents. Psychopharmacology (Berl.), 192: 159–170. Santarelli, L., Saxe, M., Gross, C., Surget, A., Battaglia, F., Dulawa, S., Weisstaub, N., Lee, J., Duman, R., Arancio, O., Belzung, C. and Hen, R. (2003) Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science, 301: 805–809. Savelieva, K.V., Zhao, S., Pogorelov, V.M., Rajan, I., Yang, Q., Cullinan, E. and Lanthorn, T.H. (2008) Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants. PLoS ONE, 3: e3301. Schechter, L.E., Lin, Q., Smith, D.L., Zhang, G., Shan, Q., Platt, B., Brandt, M.R., Dawson, L.A., Cole, D., Bernotas, R., Robichaud, A., Rosenzweig-Lipson, S. and Beyer, C.E. (2008) Neuropharmacological profile of novel and selective 5-HT6 receptor agonists: WAY-181187 and WAY-208466. Neuropsychopharmacology, 33: 1323–1335. Scruggs, J.L., Schmidt, D. and Deutch, A.Y. (2003) The hallucinogen 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI) increases cortical extracellular glutamate levels in rats. Neurosci. Lett., 346: 137–140. Seligman, M.E., Rosellini, R.A. and Kozak, M.J. (1975) Learned helplessness in the rat: time course, immunization, and reversibility. J. Comp. Physiol. Psychol., 88: 542–547. Serretti, A. and Artioli, P. (2004) The pharmacogenomics of selective serotonin reuptake inhibitors. Pharmacogenomics J., 4: 233–244.

The Role of Serotonin in Depression Shen, C., Li, H. and Meller, E. (2002) Repeated treatment with antidepressants differentially alters 5-HT1A agoniststimulated [35S]GTP gamma S binding in rat brain regions. Neuropharmacology, 42: 1031–1038. Sherman, A.D. and Petty, F. (1980) Neurochemical basis of the action of antidepressants on learned helplessness. Behav. Neural Biol., 30: 119–134. Singh, A. and Lucki, I. (1993) Antidepressant-like activity of compounds with varying efficacy at 5-HT1A receptors. Neuropharmacology, 32: 331–340. Smriga, M. and Torii, K. (2003) L-Lysine acts like a partial serotonin receptor 4 antagonist and inhibits serotonin-mediated intestinal pathologies and anxiety in rats. Proc. Natl. Acad. Sci. USA, 100: 15370–15375. Song, C. and Leonard, B.E. (2005) The olfactory bulbectomised rat as a model of depression. Neurosci. Biobehav. Rev., 29: 627–647. Steru, L., Chermat, R., Thierry, B. and Simon, P. (1985) The tail suspension test: a new method for screening antidepressants in mice. Psychopharmacology (Berl.), 85: 367–370. Stockmeier, C.A. (2003) Involvement of serotonin in depression: evidence from postmortem and imaging studies of serotonin receptors and the serotonin transporter. J. Psychiatr. Res., 37: 357–373. Stout, S.C., Owens, M.J. and Nemeroff, C.B. (1996) CRF1 receptor binding, mRNA expression and signal transduction after chronic antidepressant treatment in rats. In: Society for Neuroscience Annual Meeting. Svenningsson, P., Chergui, K., Rachleff, I., Flajolet, M., Zhang, X., El Yacoubi, M., Vaugeois, J.M., Nomikos, G.G. and Greengard, P. (2006) Alterations in 5-HT1B receptor function by p11 in depression-like states. Science, 311: 77–80. Svenningsson, P., Tzavara, E.T., Qi, H., Carruthers, R., Witkin, J.M., Nomikos, G.G. and Greengard, P. (2007) Biochemical and behavioral evidence for antidepressant-like effects of 5HT6 receptor stimulation. J. Neurosci., 27: 4201–4209. Tatarczynska, E., Klodzinska, A., Stachowicz, K. and Chojnacka-Wojcik, E. (2004) Effect of combined administration of 5-HT1A or 5-HT1B/1D receptor antagonists and antidepressants in the forced swimming test. Eur. J. Pharmacol., 487: 133–142. Tordera, R.M., Monge, A., Del Rio, J. and Lasheras, B. (2002) Antidepressant-like activity of VN2222, a serotonin reuptake

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inhibitor with high affinity at 5-HT1A receptors. Eur. J. Pharmacol., 442: 63–71. Van Den Bogaert, A., De Zutter, S., Heyrman, L., Mendlewicz, J., Adolfsson, R., Van Broeckhoven, C. and Del-Favero, J. (2005) Response to Zhang et al. (2005): loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron, 45: 11–16. Neuron 48: 704; author reply 705–706 Wesolowska, A., Nikiforuk, A., Stachowicz, K. and Tatarczynska, E. (2006) Effect of the selective 5-HT7 receptor antagonist SB 269970 in animal models of anxiety and depression. Neuropharmacology, 51: 578–586. Wesolowska, A. and Nikiforuk, A. (2007) Effects of the brainpenetrant and selective 5-HT6 receptor antagonist SB-399885 in animal models of anxiety and depression. Neuropharmacology, 52: 1274–1283. Wesolowska, A., Nikiforuk, A. and Stachowicz, K. (2007) Anxiolytic-like and antidepressant-like effects produced by the selective 5-HT6 receptor antagonist SB-258585 after intrahippocampal administration to rats. Behav. Pharmacol., 18: 439–446. Willner, P. (1997) Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation. Psychopharmacology (Berl.), 134: 319–329. Willner, P. (2005) Chronic mild stress (CMS) revisited: consistency and behavioural–neurobiological concordance in the effects of CMS. Neuropsychobiology, 52: 90–110. Zhang, X., Gainetdinov, R.R., Beaulieu, J.M., Sotnikova, T.D., Burch, L.H., Williams, R.B., Schwartz, D.A., Krishnan, K.R. and Caron, M.G. (2005) Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron, 45: 11–16. Zhou, Z., Peters, E.J., Hamilton, S.P., McMahon, F., Thomas, C., McGrath, P.J., Rush, J., Trivedi, M.H., Charney, D.S., Roy, A., Wisniewski, S., Lipsky, R. and Goldman, D. (2005) Response to Zhang et al. (2005): loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron, 45: 11–16. , Neuron 48: 702–703; author reply 705–706. Zhuang, X., Gross, C., Santarelli, L., Compan, V., Trillat, A.C. and Hen, R. (1999) Altered emotional states in knockout mice lacking 5-HT1A or 5-HT1B receptors. Neuropsychopharmacology, 21: 52S–60S.