Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

doi:10.1016/j.neubiorev.2008.03.006

Neuroscience & Biobehavioral Reviews

Volume 32, Issue 7, September 2008, Pages 1293-1314

https://doi.org/10.1016/j.neubiorev.2008.03.006 Get rights and content

Abstract

The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research.

Introduction

The work of Graeff et al. has contributed greatly to our understanding of the role of serotonin (5-hydroxytryptamine) in orchestrating the behavioral response to psychological stress (Graeff et al., 1996). Their work adds to a large corpus of data compiled over the past couple of decades which has uncovered the major enzymes, transporters and receptors that subserve the serotonergic system's modulation of both the acute response to stress and the adaptation to chronic stress. In concert, a more nascent literature has begun to identify sources of genetic variation within these molecules. These parallel lines of research have led to new ways of thinking about how genetically driven differences in serotonin function might predispose certain individuals to stress-related neuropsychiatric conditions such as depression and anxiety disorders and how we can better identify and therapeutically treat these people.

The present article provides an update on this rapidly growing field. The focus is studies that have utilized mice with modifications in serotonin genes to assess stress-related phenotypes. These data are placed in the context of salient pharmacological, neurochemical and electrophysiological findings in both rats and mice and, where applicable, findings of genetic influences from studies in humans. The review is also limited in focus to a neural circuit connecting the serotonergic dorsal raphe nucleus to the medial prefrontal cortex (mPFC) and amygdala, given growing evidence implicating this circuit in rodent stress-related responses and human stress-related disease (Drevets, 2001, Ressler and Mayberg, 2007). For a discussion of the mesencephalic tectum system as a site of serotonin's stress-related actions (see Graeff, 2004) and accompanying articles in this Special Issue. There have also been a number of excellent recent reviews dealing with the theme of serotonin genetics and stress, and the reader is referred to these for a complimentary perspective (Ansorge et al., 2007, Gross and Hen, 2004, Joca et al., 2007, Lucki, 1998, Maier et al., 2006, Neumeister et al., 2004a, Southwick et al., 2005). Lastly, for a comprehensive review of the pharmacology of serotonin's stress-related actions see Griebel, 1995, Menard and Treit, 1999, Millan, 2003.

Section snippets

Serotonin release

Serotonin is a major modulatory neurotransmitter, the actions of which are determined by various synthesizing and catabolizing enzymes, pre- and post-synaptic receptors, and molecules controlling intracellular trafficking and extracellular transport (Fig. 1). Serotonin producing neurons originate in the dorsal and median raphe nuclei located in the midbrain (Dahlstrom and Fuxe, 1964). Despite there being few serotonin neurons relative to total neuron number in brain (Jacobs and Azmitia, 1992),

Serotonin synthesis

The magnitude of stress-induced serotonin release will be dependent in part on the amount of serotonin available in the presynaptic terminal. In rodent, the synthesis of serotonin from L-tryptophan (McGeer and McGeer, 1973) in the brain is controlled by the rate-limiting enzyme tryptophan hydroxylase type 2 (Tph2) (Walther and Bader, 2003). Inhibition of Tph2 activity by chemical agents such as para-chlorophenylalanine methyl ester hydrochloride (PCPA) markedly decreases levels of serotonin (

Serotonin vesicular packaging

Following its synthesis, serotonin must be properly packaged into secretory vesicles and transported to the presynaptic terminal prior to release. The vesicular monoamine transporter type 2 (VMAT2) has an important role in this process (Hoffman et al., 1998). An early indication that VMAT2 might contribute to stress-related pathology stemmed from the serendipitous discovery that pharmacological inhibition of VMAT by reserpine treatment produced striking depressive-like symptoms in humans (

Serotonin reuptake

Serotonin released as a result of stress will be removed from the extracellular space by the high-affinity serotonin transporter (SERT, 5-HTT). SERT has an important role in determining the magnitude and duration of serotonin's activity on its presynaptic and postsynaptic receptors, because while other monoamine transporters can take up serotonin under certain conditions, SERT is the principal active means of removing substrate from the synaptic space (Blakely et al., 1991) and has a

Serotonin degradation

Serotonin cleared from the extracellular space by SERT and returned to the cell undergoes oxidative deamination into inert metabolites by the mitochondrial enzyme monoamine oxidase A (MAOA). The rate at which MAOA degrades serotonin is therefore another determinant of serotonin availability (Shih et al., 1999). MAOA inhibitors were some of the first drugs to exert demonstrable antidepressant activity in humans (Klein and Fink, 1962). Treatment with these drugs increases serotonin tissue levels

Role of 5-HT1A receptors

Serotonin released into the extracellular space acts at multiple pre-synaptic and post-synaptic located receptors that are organized in a hugely complex pattern of regional and subcellular distribution. For excellent overviews of serotonin receptor pharmacology and signaling mechanisms (see Barnes and Sharp, 1999, Hoyer et al., 2002, Kroeze and Roth, 1998).

The 5-HT1A-R subserves two critical roles within the serotonin system in regards to stress—as an autoreceptor regulating DRN neuron activity

5-HT1B receptors

5-HT1B-Rs serve as terminal presynaptic autoreceptors regulating serotonin release and as heteroreceptors on non-serotonin neurons (Moret and Briley, 1997, Morikawa et al., 2000). The autoreceptor function of 5-HT1B-Rs is exemplified by the augmentation of stimulated-increases in ECF serotonin levels in forebrain regions by pharmacological antagonism or gene knockout of the receptor (Ase et al., 2000, de Groote et al., 2002a, de Groote et al., 2002b, Knobelman et al., 2001a, Knobelman et al.,

5-HT2A receptors

Although distributed in various corticolimbic regions, there is accumulating evidence that 5-HT2A-Rs play a particularly important role in mediating serotonin's action in the mPFC during stress. 5-HT2A-R are located on the dendrites of glutamatergic pyramidal neurons and interneurons in the rodent mPFC (Aghajanian and Marek, 1997, Cornea-Hebert et al., 1999, Hamada et al., 1998, Jansson et al., 2001, Miner et al., 2003, Willins et al., 1997, Xu and Pandey, 2000). Electrophysiological studies

5-HT2C receptors

5-HT2C-Rs are highly expressed in the mPFC and amygdala (Abramowski et al., 1995, Clemett et al., 2000, Li et al., 2003, Lopez-Gimenez et al., 2002, Molineaux et al., 1989, Pompeiano et al., 1994, Sharma et al., 1997, Wright et al., 1995). Pharmacological studies point to a role for this receptor subtype in mediating serotonin's pro-anxiety effects at the level of the amygdala. Treatment with the non-specific serotonin receptor agonist m-chlorophenylpiperazine (mCPP) has potent anxiogenic

5-HT3 receptors

The 5-HT3-R distinguishes itself from other members of the 5-HT receptor family by being a ligand-gated ion channel (as opposed to a G-protein-coupled receptor) (Derkach et al., 1989) and by being largely expressed in the rodent brain as a presynaptic heteroreceptor on non-serotonergic neurons, including GABA interneurons in the mPFC and amygdala (Kilpatrick et al., 1987, Morales et al., 1998, Morales and Bloom, 1997, Tecott et al., 1993). Systemic administration of 5-HT3-R antagonists such

5-HT4, 5-HT5A, 5-HT6, and 5-HT7 receptors

This review has largely focused on the 5-HT1, 5-HT2 and 5-HT3 receptor classes because other receptor subtypes have been relatively less well studied due to their recent cloning or a lack of well-defined research tools such as subtype-selective ligands or gene mutant mice. Of course, this does not necessarily imply that these subtypes play any less of a role in modulating serotonin's stress-related actions. In fact there are promising leads for a number of subtypes expressed in the

Summary and concluding remarks

The large literature from preclinical studies in rodents indicates that genetically driven functional disruption at all levels of the serotonin system – from prenatal development to neurotransmission in the adult brain – can influence the behavioral, physiological and neuroendocrinological response to stress. While the field is still at an early stage and there is much yet to be clarified, advances have been made in defining the contributions of key molecules within the serotonin system. At the

Acknowledgments

I would like to thank Ahmad Hariri, John F. Cryan, Patrick Fisher, and David Goldman for valuable discussion and comments during the preparation of this article. Supported by the National Institute on Alcohol Abuse and Alcoholism Intramural Research Program.

References (489)

W.M. Abi-Saab et al.
5-HT2 receptor regulation of extracellular GABA levels in the prefrontal cortex
Neuropsychopharmacology
(1999)
D. Abramowski et al.
Localization of the 5-hydroxytryptamine2C receptor protein in human and rat brain using specific antisera
Neuropharmacology
(1995)
J.K. Abrams et al.
Serotonergic systems associated with arousal and vigilance behaviors following administration of anxiogenic drugs
Neuroscience
(2005)
R. Adamec et al.
Vulnerability to mild predator stress in serotonin transporter knockout mice
Behav. Brain Res.
(2006)
A. Adell et al.
Comparative study in the rat of the actions of different types of stress on the release of 5-HT in raphe nuclei and forebrain areas
Neuropharmacology
(1997)
G.K. Aghajanian et al.
Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells
Neuropharmacology
(1997)
G.K. Aghajanian et al.
Serotonin, via 5-HT2A receptors, increases EPSCs in layer V pyramidal cells of prefrontal cortex by an asynchronous mode of glutamate release
Brain Res.
(1999)
J. Amat et al.
Escapable and inescapable stress differentially alter extracellular levels of 5-HT in the basolateral amygdala of the rat
Brain Res.
(1998)
J. Amat et al.
The role of the habenular complex in the elevation of dorsal raphe nucleus serotonin and the changes in the behavioral responses produced by uncontrollable stress
Brain Res.
(2001)
M.S. Ansorge et al.
Neurodevelopmental origins of depressive disorders
Curr. Opin. Pharmacol.
(2007)

R. Araneda et al.

5-Hydroxytryptamine2 and 5-hydroxytryptamine 1A receptors mediate opposing responses on membrane excitability in rat association cortex

Neuroscience

(1991)

S. Aznar et al.

The 5-HT1A serotonin receptor is located on calbindin- and parvalbumin-containing neurons in the rat brain

Brain Res.

(2003)

N.M. Barnes et al.

A review of central 5-HT receptors and their function

Neuropharmacology

(1999)

C. Belzung et al.

Measuring normal and pathological anxiety-like behaviour in mice: a review

Behav. Brain Res.

(2001)

S. Bhatnagar et al.

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.

(2004)

S. Bhatnagar et al.

Changes in anxiety-related behaviors and hypothalamic–pituitary–adrenal activity in mice lacking the 5-HT-3A receptor

Physiol. Behav.

(2004)

M.A. Blackshear et al.

Adaptive changes in the 5-HT2 binding site after chronic administration of agonists and antagonists

Neuropharmacology

(1986)

P. Blier et al.

Current advances and trends in the treatment of depression

Trends Pharmacol. Sci.

(1994)

P. Blier et al.

Is there a role for 5-HT1A agonists in the treatment of depression?

Biol. Psychiatry

(2003)

M.E. Blue et al.

Correspondence between 5-HT2 receptors and serotonergic axons in rat neocortex

Brain Res.

(1988)

F. Bolanos-Jimenez et al.

Effects of stress on the functional properties of pre- and postsynaptic 5-HT1B receptors in the rat brain

Eur. J. Pharmacol.

(1995)

J.A. Bouwknecht et al.

Absence of 5-HT(1B) receptors is associated with impaired impulse control in male 5-HT(1B) knockout mice

Biol. Psychiatry

(2001)

J.M. Boyce-Rustay et al.

Chronic swim stress alters sensitivity to acute behavioral effects of ethanol in mice

Physiol. Behav.

(2007)

N.S. Buckholtz et al.

Daily LSD administration selectively decreases serotonin2 receptor binding in rat brain

Eur. J. Pharmacol.

(1985)

N.S. Burghardt et al.

Acute selective serotonin reuptake inhibitors increase conditioned fear expression: blockade with a 5-HT(2C) receptor antagonist

Biol. Psychiatry

(2007)

N.S. Burghardt et al.

The selective serotonin reuptake inhibitor citalopram increases fear after acute treatment but reduces fear with chronic treatment: a comparison with tianeptine

Biol. Psychiatry

(2004)

X. Cai et al.

Serotonin 5-HT1A receptors regulate AMPA receptor channels through inhibiting Ca²⁺/calmodulin-dependent kinase II in prefrontal cortical pyramidal neurons

J. Biol. Chem.

(2002)

B.M. Campbell et al.

Serotonin 2C receptors within the basolateral amygdala induce acute fear-like responses in an open-field environment

Brain Res.

(2003)

D.T. Chalmers et al.

Comparative anatomical distribution of 5-HT1A receptor mRNA and 5-HT1A binding in rat brain—a combined in situ hybridisation/in vitro receptor autoradiographic study

Brain Res.

(1991)

F. Chaouloff et al.

Effects of chlorisondamine and restraint on cortical [³H]ketanserin binding, 5-HT2A receptor-mediated head shakes, and behaviours in models of anxiety

Neuropharmacology

(1994)

J.M. Chou-Green et al.

Repeated stress in young and old 5-HT(2C) receptor knockout mice

Physiol. Behav.

(2003)

L. Christiansen et al.

Candidate gene polymorphisms in the serotonergic pathway: influence on depression symptomatology in an elderly population

Biol. Psychiatry

(2007)

J.A. Clark et al.

Differential hormonal regulation of tryptophan hydroxylase-2 mRNA in the murine dorsal raphe nucleus

Biol. Psychiatry

(2005)

M.S. Clark et al.

Increased expression of 5-HT1B receptor in dorsal raphe nucleus decreases fear-potentiated startle in a stress dependent manner

Brain Res.

(2004)

Y. Clement et al.

An autoradiographic study of serotonergic receptors in a murine genetic model of anxiety-related behaviors

Brain Res.

(1996)

D.A. Clemett et al.

Immunohistochemical localisation of the 5-HT2C receptor protein in the rat CNS

Neuropharmacology

(2000)

J.C. Compaan et al.

Pretreatment with 5-HT1A receptor agonist flesinoxan attenuates Fos protein in rat hypothalamus

Eur. J. Pharmacol.

(1997)

A.M. Cornelio et al.

Anxiogenic-like effects of mCPP microinfusions into the amygdala (but not dorsal or ventral hippocampus) in mice exposed to elevated plus-maze

Behav. Brain Res.

(2007)

J.K. Abrams et al.

Anatomic and functional topography of the dorsal raphe nucleus

Ann. NY Acad. Sci.

(2004)

Y. Akagawa et al.

Effects of repeated selective serotonin reuptake inhibitor paroxetine treatments on mouse forced swimming

Methods Find. Exp. Clin. Pharmacol.

(1999)

C. Alexandre et al.

Early life blockade of 5-hydroxytryptamine 1A receptors normalizes sleep and depression-like behavior in adult knock-out mice lacking the serotonin transporter

J. Neurosci.

(2006)

M. Amargos-Bosch et al.

Antipsychotic drugs reverse the AMPA receptor-stimulated release of 5-HT in the medial prefrontal cortex

J. Neurochem.

(2007)

M. Amargos-Bosch et al.

Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal neurons of prefrontal cortex

Cereb. Cortex

(2004)

J. Amat et al.

Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus

Nat. Neurosci.

(2005)

S.L. Andersen et al.

Differences in behavior and monoamine laterality following neonatal clomipramine treatment

Dev. Psychobiol.

(2002)

M. Anguelova et al.

A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter. II. Suicidal behavior

Mol. Psychiatry

(2003)

M. Anguelova et al.

A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter. I. Affective disorders

Mol. Psychiatry

(2003)

H. Anisman et al.

Psychogenic, neurogenic, and systemic stressor effects on plasma corticosterone and behavior: mouse strain-dependent outcomes

Behav. Neurosci.

(2001)

M.S. Ansorge et al.

Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice

J. Neurosci.

(2008)

M.S. Ansorge et al.

Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice

Science

(2004)

Cited by (226)

Neonatal nociceptive stimulation results in pain sensitization, reduction of hippocampal 5-HT<inf>1A</inf> receptor, and p-CREB expression in adult female rats
2024, Behavioural Brain Research
Painful invasive procedures are often performed on newborns admitted to intensive care units (ICU). The acute and long-term effects caused by these stimuli can be investigated in animal models, such as newborn rats. Previous studies have shown that animals subjected to nociceptive stimuli in the neonatal period show sex-specific behavioral changes such as signs of anxiety or depression. Under the same conditions, neonatal stimuli also provoke an increase in the rate of neurogenesis and cell activation in the hippocampal dentate gyrus. So, this study aims to identify the possible roles of central monoamines, receptor expression (5-HT_1A), and signaling factors (p-CREB) underlying the long-term effects of neonatal nociceptive stimulation. For this, noxious stimulation was induced by intra-plantar injection of Complete Freund´s adjuvant (CFA) on the postnatal day 1 (P1) or 8 (P8). Control animals were not stimulated. On P75 the behavioral tests were conducted (hotplate and elevated plus maze), followed by sacrifice and molecular studies. Our results showed that neonatal nociceptive stimulation alters pain sensitization specially in females, while stimulation on P1 increases pain threshold, P8-stimulated animals respond with reduced pain threshold (P < 0.001). Hippocampal expression of 5-HT_1A receptor and p-CREB were reduced in P8 F group (P < 0.001) in opposition to the increased utilization rate of dopamine and serotonin in this group (P < 0.05). This study shows sex- and age-specific responses of signaling pathways within the hippocampus accompanied by altered behavioral repertoire, at long-term after neonatal painful stimulation.
The relationship between depression, anxiety and lower urinary tract symptoms in men
2024, Prostate International
Patients with lower urinary tract symptoms (LUTS) often experience comorbid depression and anxiety, yet the mechanisms underlying this association remain incompletely understood. This prospective study aimed to investigate the relationship between depression, anxiety, and LUTS in men.
A prospective study was conducted with 350 male patients who underwent urologic examinations at our institution from January 2021 to December 2021. Of these, 131 patients meeting the inclusion criteria were included. Various questionnaires, including the International Prostate Symptom Score (IPSS) and the Hospital Anxiety and Depression Scale (HADS), as well as LUTS examinations (prostate-specific antigen test, transrectal ultrasonography, and urine flowmetry), were administered.
Among the 350 patients, 131 were included in the analysis, with an average age of 58.0 ± 13.69 years. The total IPSS was 18.0 ± 8.69, with the average voiding symptom score at 8.7 ± 5.19 and the average storage symptom score at 6.0 ± 3.27. Both anxiety and depression were found to be correlated with LUTS (P < 0.05). After adjusting for age, hypertension, and diabetes, anxiety (but not depression) was significantly associated with LUTS based on regression analysis.
Men with LUTS are more likely to experience anxiety. Therefore, it is essential to assess and address anxiety when managing men with LUTS.
Epigenetic modification of the hypothalamic–pituitary–adrenal (HPA) axis during development in the house sparrow (Passer domesticus)
2023, General and Comparative Endocrinology
Epigenetic modifications such as DNA methylation are important mechanisms for mediating developmental plasticity, where ontogenetic processes and their phenotypic outcomes are shaped by early environments. In particular, changes in DNA methylation of genes within the hypothalamic–pituitary–adrenal (HPA) axis can impact offspring growth and development. This relationship has been well documented in mammals but is less understood in other taxa. Here, we use target-enriched enzymatic methyl sequencing (TEEM-seq) to assess how DNA methylation in a suite of 25 genes changes over development, how these modifications relate to the early environment, and how they predict differential growth trajectories in the house sparrow (Passer domesticus). We found that DNA methylation changes dynamically over the postnatal developmental period: genes with initially low DNA methylation tended to decline in methylation over development, whereas genes with initially high DNA methylation tended to increase in methylation. However, sex-specific differentially methylated regions (DMRs) were maintained across the developmental period. We also found significant differences in post-hatching DNA methylation in relation to hatch date, with higher levels of DNA methylation in nestlings hatched earlier in the season. Although these differences were largely absent by the end of development, a number of DMRs in HPA-related genes (CRH, MC2R, NR3C1, NR3C2, POMC)—and to a lesser degree HPG-related genes (GNRHR2)—predicted nestling growth trajectories over development. These findings provide insight into the mechanisms by which the early environment shapes DNA methylation in the HPA axis, and how these changes subsequently influence growth and potentially mediate developmental plasticity.
Alleviating anxiety and taming trauma: Novel pharmacotherapeutics for anxiety disorders and posttraumatic stress disorder
2023, Neuropharmacology
Psychiatric disorders associated with psychological trauma, stress and anxiety are a highly prevalent and increasing cause of morbidity worldwide. Current therapeutic approaches, including medication, are effective in alleviating symptoms of anxiety disorders and posttraumatic stress disorder (PTSD), at least in some individuals, but have unwanted side-effects and do not resolve underlying pathophysiology. After a period of stagnation, there is renewed enthusiasm from public, academic and commercial parties in designing and developing drug treatments for these disorders. Here, we aim to provide a snapshot of the current state of this field that is written for neuropharmacologists, but also practicing clinicians and the interested lay-reader. After introducing currently available drug treatments, we summarize recent/ongoing clinical assessment of novel medicines for anxiety and PTSD, grouped according to primary neurochemical targets and their potential to produce acute and/or enduring therapeutic effects. The evaluation of putative treatments targeting monoamine (including psychedelics), GABA, glutamate, cannabinoid, cholinergic and neuropeptide systems, amongst others, are discussed. We emphasize the importance of designing and clinically assessing new medications based on a firm understanding of the underlying neurobiology stemming from the rapid advances being made in neuroscience. This includes harnessing neuroplasticity to bring about lasting beneficial changes in the brain rather than – as many current medications do – produce a transient attenuation of symptoms, as exemplified by combining psychotropic/cognitive enhancing drugs with psychotherapeutic approaches. We conclude by noting some of the other emerging trends in this promising new phase of drug development.
Associations between the kynurenine pathway and the brain in patients with major depressive disorder—A systematic review of neuroimaging studies
2023, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Previous studies have indicated that an imbalance in the kynurenine (KYN) pathway is an important pathophysiological mechanism of depression. Several studies have reported that an imbalance in the KYN pathway and its metabolites is associated with abnormalities in cerebral structure and function in depression, but the available evidence has been inconsistent. In this review, we systematically reviewed and integrated the findings concerning the associations between the KYN pathway and the brain in patients with major depressive disorder (MDD). A total of 22 neuroimaging studies were ultimately included in the present study. The neuroimaging modalities used in the studies included structural magnetic resonance imaging (MRI), diffusion tensor imaging, functional MRI, magnetic resonance spectroscopy, arterial spin labelling and positron emission tomography. The results revealed that an imbalance in the KYN pathway was associated with structural and functional abnormalities in several brain regions in patients with MDD. The brain regions most frequently associated with an imbalance in the KYN pathway were cortical regions (i.e., anterior cingulate cortex and orbitofrontal cortex), subcortical regions (i.e., striatum, thalamus and amygdala) and white matter fibres (i.e., inner capsule and left superior longitudinal tract). Our study provides robust evidence that cerebral abnormalities associated with the KYN pathway may be the underlying pathophysiological mechanisms of MDD. Future prospective studies are needed to further elucidate the causal relationships between the imbalanced KYN pathway and cerebral abnormalities in patients with MDD.
Beyond appetite: Acylated ghrelin as a learning, memory and fear behavior-modulating hormone
2022, Neuroscience and Biobehavioral Reviews
Although often referred to as a hunger hormone, recent evidence highlights a neuroprotective function of acylated ghrelin (AG) and a substantial role in the regulation of declarative and aversive memories as well as fear behavior. As such, in this review, we i) evaluate what specific stages and forms of memory, as well as which respective brain areas are affected by acylated ghrelin, ii) illustrate the plasticity-associated signaling pathways of AG in the hippocampus, also involving memory resolution-enhancing neurogenesis, iii) elucidate how the peptide modulates neurotransmitter systems (glutamate, γ-aminobutyric acid, dopamine, serotonin), iV) clarify the role of AG in conditioned taste aversion, novelty learning and the formation of spatial, recognition, auditory fear, contextual fear and passive avoidance memories in the hippocampus and amygdala as well as V) solve the mystery behind AG, its impact on the 5-HT system, the recently established link to post-traumatic stress disorder and the either fear-suppressing or fear-potentiating effects under neutral and acutely stressed conditions or chronic stress, respectively.

View all citing articles on Scopus

View full text

Published by Elsevier Ltd.

ReviewGenetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Abstract

Introduction

Section snippets

Serotonin release

Serotonin synthesis

Serotonin vesicular packaging

Serotonin reuptake

Serotonin degradation

Role of 5-HT1A receptors

5-HT1B receptors

5-HT2A receptors

5-HT2C receptors

5-HT3 receptors

5-HT4, 5-HT5A, 5-HT6, and 5-HT7 receptors

Summary and concluding remarks

Acknowledgments

Neuropsychopharmacology

Neuropharmacology

Neuroscience

Behav. Brain Res.

Neuropharmacology

Neuropharmacology

Brain Res.

Brain Res.

Brain Res.

Curr. Opin. Pharmacol.

Neuroscience

Brain Res.

Neuropharmacology

Behav. Brain Res.

Behav. Brain Res.

Physiol. Behav.

Neuropharmacology

Trends Pharmacol. Sci.

Biol. Psychiatry

Brain Res.

Eur. J. Pharmacol.

Biol. Psychiatry

Physiol. Behav.

Eur. J. Pharmacol.

Biol. Psychiatry

Biol. Psychiatry

J. Biol. Chem.

Brain Res.

Brain Res.

Neuropharmacology

Physiol. Behav.

Biol. Psychiatry

Biol. Psychiatry

Brain Res.

Brain Res.

Neuropharmacology

Eur. J. Pharmacol.

Behav. Brain Res.

Anatomic and functional topography of the dorsal raphe nucleus

Ann. NY Acad. Sci.

Effects of repeated selective serotonin reuptake inhibitor paroxetine treatments on mouse forced swimming

Methods Find. Exp. Clin. Pharmacol.

Early life blockade of 5-hydroxytryptamine 1A receptors normalizes sleep and depression-like behavior in adult knock-out mice lacking the serotonin transporter

J. Neurosci.

Antipsychotic drugs reverse the AMPA receptor-stimulated release of 5-HT in the medial prefrontal cortex

J. Neurochem.

Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal neurons of prefrontal cortex

Cereb. Cortex

Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus

Nat. Neurosci.

Differences in behavior and monoamine laterality following neonatal clomipramine treatment

Dev. Psychobiol.

A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter. II. Suicidal behavior

Mol. Psychiatry

A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter. I. Affective disorders

Mol. Psychiatry

Psychogenic, neurogenic, and systemic stressor effects on plasma corticosterone and behavior: mouse strain-dependent outcomes

Behav. Neurosci.

Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice

J. Neurosci.

Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice

Science

Review
Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease