Dysfunctional Heteroreceptor Complexes as Novel Targets for the Treatment of Major Depressive and Anxiety Disorders.

Among mental diseases, major depressive disorder (MDD) and anxiety deserve a special place due to their high prevalence and their negative impact both on society and patients suffering from these disorders. Consequently, the development of novel strategies designed to treat them quickly and efficiently, without or at least having limited side effects, is considered a highly important goal. Growing evidence indicates that emerging properties are developed on recognition, trafficking, and signaling of G-protein coupled receptors (GPCRs) upon their heteromerization with other types of GPCRs, receptor tyrosine kinases, and ionotropic receptors such as N-methyl-D-aspartate (NMDA) receptors. Therefore, to develop new treatments for MDD and anxiety, it will be important to identify the most vulnerable heteroreceptor complexes involved in MDD and anxiety. This review focuses on how GPCRs, especially serotonin, dopamine, galanin, and opioid heteroreceptor complexes, modulate synaptic and volume transmission in the limbic networks of the brain. We attempt to provide information showing how these emerging concepts can contribute to finding new ways to treat both MDD and anxiety disorders.

Changes in Intestinal Microbiota and Predicted Metabolic Pathways During Colonic Fermentation of Mango (Mangifera indica L.)-Based Bar Indigestible Fraction.

Mango (Mangifera indica L.) peel and pulp are a source of dietary fiber (DF) and phenolic compounds (PCs) that constituent part of the indigestible fraction (IF). This fraction reaches the colon and acts as a carbon and energy source for intestinal microbiota. The effect of mango IF on intestinal microbiota during colonic fermentation is unknown. In this study, the isolated IF of a novel 'Ataulfo' mango-based bar (snack) UV-C irradiated and non-irradiated (UVMangoB and MangoB) were fermented. Colonic fermentation occurred in vitro under chemical-enzymatic, semi-anaerobic, batch culture and controlled pH colonic conditions. Changes in the structure of fecal microbiota were analyzed by 16s rRNA gene Illumina MiSeq sequencing. The community´s functional capabilities were determined in silico. The MangoB and UVMangoB increased the presence of Faecalibacterium, Roseburia, Eubacterium, Fusicatenibacter, Holdemanella, Catenibacterium, Phascolarctobacterium, Buttiauxella, Bifidobacterium, Collinsella, Prevotella and Bacteroides genera. The alpha indexes showed a decrease in microbial diversity after 6 h of colonic fermentation. The coordinates analysis indicated any differences between irradiated and non-irradiated bar. The metabolic prediction demonstrated that MangoB and UVMangoB increase the microbiota carbohydrate metabolism pathway. This study suggests that IF of mango-based bar induced beneficial changes on microbial ecology and metabolic pathway that could be promissory to prevention or treatment of metabolic dysbiosis. However, in vivo interventions are necessary to confirm the interactions between microbiota modulating and intestinal beneficial effects.

Conventional and Novel Pharmacological Approaches to Treat Dopamine-Related Disorders: Focus on Parkinson's Disease and Schizophrenia.

The dopaminergic system integrated by cell groups distributed in several brain regions exerts a modulatory role in brain. Particularly important for this task are the mesencephalic dopamine neurons, which from the substantia nigra and ventral tegmental area project to the dorsal striatum and the cortical/subcortical limbic systems, respectively. Dopamine released from these neurons operates mainly via the short distance extrasynaptic volume transmission and activates five different dopaminergic receptor subtypes modulating synaptic GABA and glutamate transmission. To accomplish this task dopaminergic neurons keep mutual modulating interactions with neurons of other neurotransmitter systems, including allosteric receptor-receptor interactions in heteroreceptor complexes. As a result of its modulatory role dopaminergic mechanisms are involved in either the etiology or physiopathology of many brain diseases such as Parkinsons disease and schizophrenia. The aim of this work is to review some novel and conventional approaches that either have been used or are currently employed to treat these diseases. Particular attention is paid to the approaches derived from the knowledge recently acquired in the realm of receptor-receptor interactions taking place through multiple dopamine heteroreceptor complexes in the plasma membrane. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.

Antinociceptive effect of aqueous extracts from the bark of Croton guatemalensis Lotsy in mice.

Croton guatemalensis Lotsy (CGL), known as "copalchi" in Chiapas, Mexico, is used for the treatment of fever, abdominal pain and malaria and also as a remedy for chills and for treating rheumatism. The aim of this study was to evaluate whether aqueous extracts from the bark of this plant possesses indeed antinociceptive properties by using two different animal models of nociception, the acetic acid-induced writhing test and the hot plate model. The results showed that i.p. administration of this extract (0, 100, 200 and 400 mg/kg) 30 min prior testing had significant dose-dependent antinociceptive effects in the acetic acid-induced writhing test and that the reduction of writhings (85.5 % as compared to the control) at the highest dose tested is similar to that exhibited by dipyrone (250 mg/kg). This effect was not reversed by naloxone, a non-selective opioid receptor antagonist, suggesting that the endogenous opioid system does not underlie the antinociceptive effects of CGL in the acetic acid-induced writhing test. No effects were however observed in the hot-plate model. Our results indicate that aqueous extracts from Croton guatemalensis bark contain pharmacologically active constituents endowed with antinociceptive activity. It is suggested that cyclooxygenase inhibition might be at least partially involved in the antinociceptive effects of this extract.

Pruebas no condicionadas en ratones para evaluar la actividad ansiolítica de sustancias extraídas de plantas / Non-conditioned test on mice to evaluate the anxiolytic activity of substances extracted from plants

En el último año, el Laboratorio Experimental de Farmacología de la Facultad de Medicina de la Universidad Autónoma de Chiapas (UNACH), ha venido sistematizando pruebas no condicionadas para el estudio de la ansiedad en modelos animales. En este trabajo se efectúa una revisión bibliográfica que actualiza el conocimiento sobre las pruebas útiles en la evaluación de la ansiedad. Estas pruebas las utilizamos en los trabajos de investigación de extractos vegetales con base en hallazgos etnobotánicos de la medicina tradicional chiapaneca, los cuales se han desarrollado con modestos recursos financieros de la Facultad de Medicina de la Universidad y autofinanciamiento por parte de los investigadores, considerando la generación de conocimiento y la posibilidad de ampliar las expectativas terapéuticas con recursos naturales, como el insumo de mayor valor. Además, es de interés para el equipo investigador vincular en este proceso a investigadores de otras universidades e instituciones de salud que estén estudiando compuestos extraídos de plantas y que sirvan como base en la obtención de fármacos no sintéticos para tratamiento de la ansiedad en el hombre...

In the last year the Laboratory of Experimental Pharmacobiology at the Medicine Faculty of the Universidad Autónoma de Chiapas UNACH has been setting up several non-conditioned tests for the study of anxiety in animal models. In this work a literature review updates the knowledge of useful tests in the assessment of anxiety. These tests are used in the research of plant extracts based on ethnobotanical findings of traditional medicine of Chiapas, which have been developed with modest financial resources of the Medical Faculty of the University and self-financing by the researchers, given the knowledge generation and the possibility of extending the therapeutic expectations with natural resources as the most valuable input. It is also of interest to the research team in this process to link researchers from other universities and health institutions who are studying compounds extracted from plants and serve as a basis for obtaining non-synthetic drugs for treatment of anxiety in humans...

Annomontine, an alkaloid isolated from Annona purpurea, has anxiolytic-like effects in the elevated plus-maze.

The effects of annomontine, a pyrimidine- ß-carboline alkaloid isolated from the root of ANNONA PURPUREA, on anxiety was studied in mice using the elevated plus-maze. The behavioral effects of this alkaloid on the pentobarbital-induced hypnosis, the locomotor activity in an open field, and the motor coordination in the rotarod test were also evaluated. The intraperitoneal injection of annomontine (1-30 mg/kg) increased in a dose-dependent way the number of visits to and the time spent in the open arms of the elevated plus-maze in comparison to the control animals. Such effects were blocked by the prior application of flumazenil (3 mg/kg; i. p.), a specific antagonist for the binding of benzodiazepines on the GABA (A) receptor. Under the same experimental conditions annomontine failed to affect the behavior of the animals in the pentobarbital-induced hypnosis test and had no effects on locomotion and motor coordination. These results suggest that annomontine possesses anxiolytic-like effects which may be mediated at the level of the benzodiazepine binding site on the GABA (A) receptor.