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Brain Circuits Regulated by the 5-HT2A Receptor: Behavioural Consequences on Anxiety and Fear Memory

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5-HT2A Receptors in the Central Nervous System

Part of the book series: The Receptors ((REC,volume 32))

Abstract

Anxiety disorders including generalized anxiety disorder (GAD), panic disorder (PD), social anxiety disorder (SAD) or phobias are the most prevalent mental pathologies across the world with a median lifetime prevalence of approximately 15%. Anxiety imposes substantial economic costs which are among the highest of all mental disorders studied. Evidence is now accumulating that the serotonergic nervous system is involved in the pathology of anxiety and can provide benefits in the treatment of related disorders through its diverse functions, notably the modulation of stress, fear and memory. Among serotonin receptor subtypes, the 5-HT2A receptor arouses great interest. This receptor displays original pharmacological properties i.e., cooperation with β-arrestins and homo−/hetero-dimerization regulating its intracellular signaling and its ability to control the serotonergic system. The present chapter provides insight into the mechanisms by which the 5-HT2A receptor may alter the activity of 5-HT neurons but also of the brain regions receiving a dense serotonergic innervation (i.e, the amygdala, the hippocampus and the prefrontal cortex). An overview of the literature is proposed to recapitulate the pharmacological and genetic studies in patients or relevant animal models supporting a role of the 5-HT2A receptor on various forms of anxiety. Moreover, we envision the future directions that we might follow to develop new anxiolytic strategies based on the manipulation of 5-HT2A-mediated signaling. Doing so, we also point some inconsistencies illustrating the difficulty to target this receptor as a valid alternative to benzodiazepines.

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Abbreviations

5-HT:

Serotonin

5-HT2A :

5-Hydroxytryptamine 2A

AMY:

Amygdala

BDNF:

Brain-derived neurotrophic factor

BLA:

Basolateral complex of amygdala

CeA:

Central nucleus of amygdala

CRF:

Corticotropin releasing factor

CRFR:

Corticotropin releasing factor receptor

DA:

Dopamine

DAG:

Diacylglycerol

DCX:

Doublecortin

DG:

Dentate gyrus

DR:

Dorsal raphe

EPM:

Elevated plus maze

ERK:

Extracellular signal-regulated kinase

ETM:

Elevated T-maze

FPT:

Four plate test

GAD:

Generalized anxiety disorders

GC:

Granule cell

GDNF:

Glial cell line-derived neurotrophic factor

HP:

Hippocampus

IP3 :

Inositol Triphosphate

IPSCs:

Inhibitory post-synaptic currents

LC:

Locus coeruleus

LSD:

Lysergic acid diethylamide

MeA:

Medial amygdala

mPFCx:

Medial prefrontal cortex

MR:

Median raphe

NE:

Norepinephrine

NSF:

Novelty suppressed feeding

OF:

Open field

OIC:

Object in Context Recognition Task

PAG:

Periaqueducal grey

PD:

Panic disorders

PKC:

Protein kinase C

PLC:

Phospholipase C

PV:

Parvalbumin

SAD:

Social anxiety disorder

SGZ:

Subgranular zone

SNOR:

Spontaneous Novel Object Recognition task

SNP:

Single nucleotide polymorphism

SOM:

Somatostatin

SSRIs:

Serotonin selective reuptake inhibitors

TI:

Tonic immobility

TMOR:

Temporal Order Recognition Task

Tph:

Tryptophan hydroxylase

VEGF:

Vascular endothelial growth factor

VTA:

Ventral tegmental area

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Authors and Affiliations

  1. Research Center on Animal Cognition, Center for Integrative Biology, Université Paul Sabatier, UMR 5169 CNRS, Toulouse Cedex 9, France

    L. Moulédous & P. Roullet

  2. Faculté de Pharmacie, Université Paris Sud, Université Paris-Saclay, 92290, Chatenay-Malabry, France

    Bruno P. Guiard

  3. Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université de Toulouse; CNRS, UPS, Toulouse, France

    Bruno P. Guiard

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    Bruno P. Guiard

  2. Department of Physiology and Biochemistry, University of Malta, Msida MSD, Malta

    Giuseppe Di Giovanni

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Moulédous, L., Roullet, P., Guiard, B.P. (2018). Brain Circuits Regulated by the 5-HT2A Receptor: Behavioural Consequences on Anxiety and Fear Memory. In: Guiard, B., Di Giovanni, G. (eds) 5-HT2A Receptors in the Central Nervous System. The Receptors, vol 32. Humana Press, Cham. https://doi.org/10.1007/978-3-319-70474-6_10

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