Abstract
The etiology of major depression remains unclear, but reduced activity of the serotonin (5-HT) system remains implicated and treatments that increase 5-HT neurotransmission can ameliorate depressive symptoms. 5-HT1A receptors are critical regulators of the 5- HT system. They are expressed as both presynaptic autoreceptors that negatively regulate 5-HT neurons, and as post-synaptic heteroreceptors on non-serotonergic neurons in the hippocampus, cortex, and limbic system that are critical to mediate the antidepressant actions of 5-HT. Thus, 5-HT1A auto- and heteroreceptors have opposite actions on serotonergic neurotransmission. Because most 5-HT1A ligands target both auto- and heteroreceptors their efficacy has been limited, resulting in weak or unclear responses. We propose that by understanding the transcriptional regulation of the 5-HT1A receptor it may be possible to regulate its expression differentially in raphe and projection regions. Here we review the transcriptional architecture of the 5-HT1A gene (HTR1A) with a focus on specific DNA elements and transcription factors that have been shown to regulate 5-HT1A receptor expression in the brain. Association studies with the functional HTR1A promoter polymorphism rs6295 suggest a new model for the role of the 5-HT1A receptor in susceptibility to depression involving early deficits in cognitive, fear and stress reactivity as stressors that may ultimately lead to depression. We present evidence that by targeting specific transcription factors it may be possible to oppositely regulate 5-HT1A auto- and heteroreceptor expression, synergistically increasing serotonergic neurotransmission for the treatment of depression.
Keywords: Serotonin, repressor, enhancer, antidepressant, raphe, autoreceptor.
Current Pharmaceutical Design
Title:Transcriptional Dys-regulation in Anxiety and Major Depression: 5-HT1A Gene Promoter Architecture as a Therapeutic Opportunity
Volume: 20 Issue: 23
Author(s): Paul R. Albert and Laura M. Fiori
Affiliation:
Keywords: Serotonin, repressor, enhancer, antidepressant, raphe, autoreceptor.
Abstract: The etiology of major depression remains unclear, but reduced activity of the serotonin (5-HT) system remains implicated and treatments that increase 5-HT neurotransmission can ameliorate depressive symptoms. 5-HT1A receptors are critical regulators of the 5- HT system. They are expressed as both presynaptic autoreceptors that negatively regulate 5-HT neurons, and as post-synaptic heteroreceptors on non-serotonergic neurons in the hippocampus, cortex, and limbic system that are critical to mediate the antidepressant actions of 5-HT. Thus, 5-HT1A auto- and heteroreceptors have opposite actions on serotonergic neurotransmission. Because most 5-HT1A ligands target both auto- and heteroreceptors their efficacy has been limited, resulting in weak or unclear responses. We propose that by understanding the transcriptional regulation of the 5-HT1A receptor it may be possible to regulate its expression differentially in raphe and projection regions. Here we review the transcriptional architecture of the 5-HT1A gene (HTR1A) with a focus on specific DNA elements and transcription factors that have been shown to regulate 5-HT1A receptor expression in the brain. Association studies with the functional HTR1A promoter polymorphism rs6295 suggest a new model for the role of the 5-HT1A receptor in susceptibility to depression involving early deficits in cognitive, fear and stress reactivity as stressors that may ultimately lead to depression. We present evidence that by targeting specific transcription factors it may be possible to oppositely regulate 5-HT1A auto- and heteroreceptor expression, synergistically increasing serotonergic neurotransmission for the treatment of depression.
Export Options
About this article
Cite this article as:
Albert R. Paul and Fiori M. Laura, Transcriptional Dys-regulation in Anxiety and Major Depression: 5-HT1A Gene Promoter Architecture as a Therapeutic Opportunity, Current Pharmaceutical Design 2014; 20 (23) . https://dx.doi.org/10.2174/13816128113196660740
DOI https://dx.doi.org/10.2174/13816128113196660740 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Editorial [Hot Topic: Potassium Channels (Guest Editor: Dr. Vincenzo Calderone)]
Current Topics in Medicinal Chemistry Small Molecule Modulation of p75 Neurotrophin Receptor Functions
CNS & Neurological Disorders - Drug Targets Adenosine, Ketogenic Diet and Epilepsy: The Emerging Therapeutic Relationship Between Metabolism and Brain Activity
Current Neuropharmacology MicroRNAs: Key Players in Microglia and Astrocyte Mediated Inflammation in CNS Pathologies
Current Medicinal Chemistry Genomic and Pharmacogenomic Biomarkers of Parkinson’s Disease
Current Drug Metabolism Future Directions for Pharmacotherapies for Treatment-resistant Bipolar Disorder
Current Neuropharmacology Studies on the Pathophysiology and Genetic Basis of Migraine
Current Genomics Activators and Inhibitors of the Ion Channel of the NMDA Receptor
Current Drug Targets Potential Crossreactivity of Human Immune Responses Against HCMV Glycoprotein B
Current Drug Discovery Technologies Consequences of Iron Accumulation in Microglia and its Implications in Neuropathological Conditions
CNS & Neurological Disorders - Drug Targets Lipoic Acid: A Novel Therapeutic Approach for Multiple Sclerosis and Other Chronic Inflammatory Diseases of the CNS
Endocrine, Metabolic & Immune Disorders - Drug Targets The Metabolism of Methazolamide - Identification of Metabolites in Guinea Pig Urine
Drug Metabolism Letters Pediatric Chronic Daily Headache
Current Pediatric Reviews The Effects of Creatine Supplementation and Physical Exercise on Traumatic Brain Injury
Mini-Reviews in Medicinal Chemistry Wavelet Transform Based Algorithm for Automatic Detection of Patient- Specific Single Spike-and-Wave Discharges in Simulated Real-Time Conditions
Neuroscience and Biomedical Engineering (Discontinued) Aliphatic and Aromatic Oxidations, Epoxidation and S-Oxidation of Prodrugs that Yield Active Drug Metabolites
Current Medicinal Chemistry Maternal Exposure to Quetiapine: Effects on Structural Changes in Developing Brain and its Lasting Impact on Neurobehavioral Impairments in Rat Offspring
Current Psychopharmacology Old Weapons for New Wars: Bioactive Molecules From Cnidarian Internal Defense Systems
Central Nervous System Agents in Medicinal Chemistry The Effects of Aqueous Extract of Apium Graveolens on Brain Tissues Oxidative Damage in Pentylenetetrazole-induced Seizures Model in Rat
Current Nutrition & Food Science Editorial (Thematic Issue: GABAergic Modulation as Treatment Strategy: Consideration of Several Diseases)
Current Pharmaceutical Design