Neuroplasticity and Mechanisms of Action of Acute and Chronic Treatment with Antidepressants in Preclinical Studies

Abstract

Pharmacotherapy for depression includes drugs such as monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), noradrenaline (NA) and serotonin (5-HT) reuptake inhibitors (NaSSAs), and atypical antidepressants; these drugs exert differentially beneficial effects on symptoms of depression after acute and chronic treatment in animal models. Said effects are established through neuroplastic mechanisms involving changes in neurogenesis and synaptogenesis as result of the activation of intracellular signaling pathways associated with neurochemical and behavioral changes. Antidepressants increase the synaptic availability of monoamines (monoaminergic hypothesis) such as 5-HT, NA, and gamma-aminobutyric acid (GABA) by inhibiting their reuptake or degradation and activating intracellular signaling pathways such as the responsive element binding protein (cAMP-CREB) cascade, which regulates the expression of genes related to neuroplasticity and neurogenesis, such as brain-derived neurotrophic factor (BDNF), in various brain structures implicated in depression. The aim of this review is to analyze the mechanisms of action of different antidepressants and to compare the effects of acute and chronic treatment on neuroplasticity in animal models of depression. A thorough search was conducted in PubMed, Scopus, and Web of Science, focusing on studies since 1996 with keywords like antidepressants, acute and chronic treatment, neuroplasticity, and experimental depression. Studies included had to investigate antidepressant effects experimentally, with full-text access, while excluding those that did not. Data extraction focused on study design, findings, and relevance to understanding treatment differences. Only high-quality, peer-reviewed studies were considered to ensure a comprehensive synthesis of current knowledge.

Keywords: acute and chronic treatment; antidepressants; depression; mechanisms of action; neuroplasticity; neurotrophic factors.

Figure 1

Signaling pathways activated by rapid antidepressants. Acute administration of ketamine and psychotropic drugs can activate various signaling pathways that modulate glutamate release. This mechanism is regulated by GABAergic neurons and astrocytes, which activate the transcription of BNDF and Homer1a in response to synaptic plasticity.

Figure 2

Signaling pathways that are regulated by chronic treatment with typical antidepressants such as the selective 5-hydroxytryptamine (5-HT) reuptake inhibitors (SSRIs). These block the reuptake of monoamines by the 5-HT transporter (SERT). This leads to the regulation of postsynaptic G-protein-coupled receptors coupled to a variety of second messenger systems, including the cAMP response element protein kinase A (PKA)-cAMP binding pathway (CREB). In addition, neurotrophic factor (BDNF)/tropomyosin-related kinase receptor type B (BDNF/TrkB) signaling promotes neuronal survival, plasticity, neurogenesis, and neuronal growth through activation of the MAPK/ERK (mitogen-activated protein kinases) PI3K (inositol 1,4,5-trisphosphate signaling pathways.