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.

The neurobiology of depression establishes a close relationship between this psychiatric disorder and alterations in neuroplasticity associated with neuronal atrophy and a reduction in dendritic arborization in the prefrontal cortex and hippocampus. In this sense, the therapeutic effect of antidepressants is associated with changes in the brain associated with neuroplasticity, neurogenesis and synaptogenesis through the activation of intracellular signaling pathways associated with changes at the neurochemical and behavioral level in animal models used to study depression. Antidepressants increase the synaptic availability of monoamines (monoaminergic hypothesis) such as serotonin, noradrenaline and GABA by inhibiting their reuptake or degradation and activating intracellular signaling pathways such as the cAMP-CREB cascade, which regulates the expression of genes related to neuroplasticity and neurogenesis in various brain structures associated with depression. Although acute treatment alters the number of receptors, the therapeutic effect lasts 3-4 weeks and depends on the increase in the density of dendritic spines and the expression of proteins such as BDNF and GAP-43 in the hippocampus and cerebral cortex. This review focuses on the effects of acute and chronic treatment with monoaminergic antidepressants and new drugs and other pharmacological alternatives in preclinical studies with the aim of demonstrating their mechanism of action and relationship to neuroplasticity.

Background: Premenstrual syndrome is characterized by emotional changes, including anxiety and depression symptoms, which may be treated with anxiolytic and antidepressant drugs, as well as estrogen therapy. However, steroidal estrogen therapy is contraindicated for patients with a potential risk of developing estrogen-dependent cancers through interactions with estrogen receptor α (ERα). Alternatively, genistein produces estrogenic effects in animals and humans at dietary dosages that act on the nuclear and membrane ERα, estrogen receptor β (ERβ), and the G-protein-coupled estrogen receptor (GPER). These receptors are likely involved in the anxiety symptoms observed in premenstrual disorders. The objective of this study was to evaluate the effects of genistein and 17β-estradiol on anxiety-like behavior and the plasma concentrations of estradiol and progesterone throughout the ovarian cycle of Wistar rats. Methods: The effect of the administration of 0.09 mg/kg of genistein or 17β-estradiol was evaluated using the elevated plus maze (EPM) test, locomotor activity test (LAT), and light/dark box (LDB) test, as well as by assessing the plasma concentrations of estradiol and progesterone, while considering the ovarian cycle phases. Results: Higher levels of anxiety-like behavior were detected in the metestrus–diestrus phase compared to the proestrus–estrus phase, which was associated with low concentrations of estradiol. Genistein, similarly to 17β-estradiol, significantly reduced anxiety-like behaviors in the EPM and LDB; however, 17β-estradiol, but not genistein, significantly increased the plasma estradiol concentration. No significant changes were found in locomotor activity or the plasma progesterone concentrations due to the treatments. Conclusions: These findings suggest that genistein may be useful in the development of alternative therapies to reduce the anxiety associated with low steroid hormone concentrations, which occur in premenstrual syndrome. Genistein could be an alternative to steroidal estrogen therapy to avoid potential side effects due to estradiol or antidepressant treatments, although it still requires medical care.

Anxiety is one of the most common psychopathologies in the general population that often begin early in life; however, research on this disorder during early developmental stages has been poorly explored compared to adults. A better understanding of the anxiety disorder through childhood is essential to develop more effective treatments. This chapter provides a general overview of the usefulness of animal models of childhood anxiety and its neurobiological bases to discuss how the studies on animals meet the several criteria of validity to discover pathophysiological mechanisms of human disorders and new treatments for these conditions. The research methodology for this chapter consisted in using a thesaurus system such as Medical Subject Headings (MeSH) terms of the National Library of Medicine to find original articles in databases as PubMed or Web of Science about preclinical findings related to the neuropharmacology of anxiety before adulthood. The contribution of this chapter is to provide data from preclinical studies which are encouraged to a better comprehension of anxiety at young age.

Ancient cultures have long studied plants for medicinal use. Today, multidisciplinary research focuses on re-evaluating these plants to discover drugs for treating various diseases, including psychiatric disorders. Pre-Columbian Mesoamerican cultures described three plants (Montanoa tomentosa, Montanoa frutescens, and Montanoa grandiflora) for treating both anxiety and depression disorders, which were called cihuapahtli in Nahuatl. This narrative review describes and analyzes the ethnobotanical use and phytochemical, pharmacological, behavioral, and toxicological effects of cihuapahtli, which can contribute to the discovery of anxiolytic and antidepressant drugs. The results show a significant advance in identifying bioactive phytochemicals, including triterpenes, diterpenes, monoterpenes, and sesquiterpenes, as well as sterols, flavonoids, and alkaloids. In particular, the mechanism of action underlying their anxiolytic and antidepressant effects involves the activation of oxytocinergic neurons in the paraventricular nucleus of the hypothalamus, as well as that of the GABAergic system by targeting GABA_A receptors. The three Montanoa species have the potential to help us develop anxiolytic and antidepressant drugs; however, future studies are still required to evaluate toxicity, dose standardization, possible variability in plant-derived compounds, pharmacokinetic parameters, and pharmacological interactions. Only then will preclinical evidence be sufficiently robust to justify translational studies evaluating the safety and efficacy of these plant extracts for the development of anxiolytic and antidepressant phytomedicines.

Background: Chrysin (5-7-dihydroxyflavone) exerts anxiolytic-like effects via the GABA_A/benzodiazepine receptor complex after acute administration, similar to diazepam. Chronic diazepam treatment produces pharmacological tolerance, likely due to structural receptor modification. Whether chronic chrysin treatment also produces pharmacological tolerance remains unknown. This study evaluated GABA_A/benzodiazepine receptor-mediated behavioral responses after a pharmacological challenge with a sedative dose of diazepam (5 mg/kg) in rats chronically treated with chrysin or diazepam. Methods: Thirty-five male Wistar rats were divided into five groups: vehicle, chrysin (1, 2.5, or 5 mg/kg), and diazepam (2 mg/kg, pharmacological control). Treatments were injected intraperitoneally for 32 days. On day 28, rats were evaluated in the elevated plus maze and locomotor activity tests. On day 32, all groups received a pharmacological challenge with 5 mg/kg diazepam and were assessed via sedative scale and the rota-rod test. Results: Chronic Chrysin (5 mg/kg) but not diazepam, maintained anxiolytic-like effects. No doses of chrysin showed pharmacological cross-tolerance to 5 mg/kg of diazepam, which produced incoordination and sedation, similar to vehicle. Conclusions: Chronic treatment with chrysin (5 mg/kg) maintained their anxiolytic-like effects without pharmacological tolerance or cross-tolerance, unlike diazepam. This result supports the potential anxiolytic-like effects of chrysin in the long-term, as an alternative for anxiety disorders that require chronic treatment. This could contribute to the translational studies that could be applied to humans in the future.