The aim of the study was to investigate whether the antidepressant trazodone (TRZ), a serotonin-2 receptor antagonist/reuptake inhibitor, modifies gamma-amino-butyric acid (GABA) extracellular levels in the cerebral cortex, by acting on 5-HT(2A) receptors, and through this mechanism increases 5-HT levels. For this purpose the effect of TRZ on the release of GABA was studied in adult male rats in synaptosomes, cortical slices, and "in vivo" by microdialysis. In cortical slices, the release of both GABA and 5-HT was determined. GABA and 5-HT were identified and their levels quantified by HPLC. The inhibition of 5-HT uptake by TRZ was also measured. In synaptosomes, TRZ antagonized dose-dependently, at concentrations from 10(-10) to 10(-6) M, the increase in GABA release induced by (+/-)DOI, a 5-HT(2A/2C) agonist, and the alpha receptor agonist phenylephrine, both 10(-6) M. The pIC50 values were 8.31+/-0.24, and 5.99+/-0.52, respectively. In the same preparation, [3H]5-HT accumulation was inhibited by citalopram and TRZ with pIC(50) of 7.8+/-0.44 and 5.9+/-0.09, respectively, a finding confirming the weak activity of TRZ in comparison with a SSRI. In cortical slices, TRZ exerted a biphasic effect on GABA release. At concentrations from 10(-10) to 10(-7) M it inhibited and from 10(-6) to 10(-4) M increased GABA release. 5-HT release was enhanced by TRZ throughout the entire range of concentrations tested. However, the increase was delayed after low and rapid after high concentrations. AMI-193, a 5-HT(2A) antagonist (10(-10) to 10(-5) M), reduced GABA release in a dose-response manner, while it induced an increase of 5-HT outflow. On the contrary, (+/-)DOI (10(-10) to 10(-5) M) increased GABA release and inhibited 5-HT levels. Perfusion with the GABA(A) receptor antagonist bicuculline was also followed by an increase in 5-HT release. In microdialysis experiments, TRZ 1.25 mg kg(-1) s.c. brought about a decrease in GABA extracellular levels, while an increase was found after the dose of 2.5 mg kg(-1). These findings demonstrate that TRZ, at concentrations which do not inhibit 5-HT uptake, reduces the cortical GABAergic tone by decreasing GABA extracellular levels, through the blockade of 5-HT(2A) receptors. The attenuation of GABAergic tone is responsible for an increase in 5-HT levels. A further increase also results from 5-HT uptake inhibition caused by higher doses of TRZ. The ensuing high 5-HT levels enhance GABA release, which in turn inhibits 5-HT release.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.pnpbp.2004.05.046 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Morphological and functional decline of the SNc in a model of progressive parkinsonism.
NPJ Parkinsons Dis
January 2025
Vollum Institute, Oregon Health & Science University, Portland, OR, USA.
The motor symptoms of Parkinson's Disease are attributed to the degeneration of dopamine neurons in the substantia nigra pars compacta (SNc). Previous work in the MCI-Park mouse model has suggested that the loss of somatodendritic dopamine transmission predicts the development of motor deficits. In the current study, brain slices from MCI-Park mice were used to investigate dopamine signaling in the SNc prior to and through the onset of movement deficits.
View Article and Find Full Text PDFIonic Mechanisms Involved in β3-Adrenoceptor-Mediated Augmentation of GABAergic Transmission Onto Pyramidal Neurons in Prefrontal Cortex.
J Neurochem
January 2025
School of Life Science, Nanchang University, Nanchang, China.
Activation of the brain-penetrant beta3-adrenergic receptor (Adrb3) is implicated in the treatment of depressive disorders. Enhancing GABAergic inputs from interneurons onto pyramidal cells of prefrontal cortex (PFC) represents a strategy for antidepressant therapies. Here, we probed the effects of the activation of Adrb3 on GABAergic transmission onto pyramidal neurons in the PFC using in vitro electrophysiology.
View Article and Find Full Text PDFChronic Pain and Comorbid Emotional Disorders: Neural Circuitry and Neuroimmunity Pathways.
Int J Mol Sci
January 2025
Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Chronic pain is a multidimensional experience that not only involves persistent nociception but is also frequently accompanied by significant emotional disorders, such as anxiety and depression, which complicate its management and amplify its impact. This review provides an in-depth exploration of the neurobiological mechanisms underlying the comorbidity of chronic pain and emotional disturbances. Key areas of focus include the dysregulation of major neurotransmitter systems (serotonin, gamma-aminobutyric acid, and glutamate) and the resulting functional remodeling of critical neural circuits implicated in pain processing, emotional regulation, and reward.
View Article and Find Full Text PDFChronic Rapamycin Prevents Electrophysiological and Morphological Alterations Produced by Conditional Pten Deletion in Mouse Cortex.
Cells
January 2025
IDDRC, Jane and Terry Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Article Synopsis
- Abnormalities in the mTOR pathway are linked to various brain disorders, affecting synaptic and membrane excitability in neurons.
- Using a mouse model with Pten deletion, the study found that CPNs had increased membrane size and reduced neuronal firing, which could be reversed with rapamycin treatment.
- Chronic rapamycin not only prevented changes in Pten mice but also altered the membrane properties of normal mice, suggesting potential treatments for neurological disorders like epilepsy and autism associated with mTOR dysfunction.
bFGF-Chitosan "brain glue" promotes functional recovery after cortical ischemic stroke.
Bioact Mater
April 2025
Beijing Key Laboratory for Biomaterials and Neural Regeneration, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China.
The mammalian brain has an extremely limited ability to regenerate lost neurons and to recover function following ischemic stroke. A biomaterial strategy of slowly-releasing various regeneration-promoting factors to activate endogenous neurogenesis represents a safe and practical neuronal replacement therapy. In this study, basic fibroblast growth factor (bFGF)-Chitosan gel is injected into the stroke cavity.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!