Modulation of synaptic transmission in nucleus accumbens core by the activation of 5-HT₂ᴀ receptor in male mice

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dc.contributor.advisorFuenzalida Núñez, Marco
dc.contributor.advisorProfesor co-guía: Sotomayor-Zárate, Ramón
dc.contributor.authorEstay Olmos, Camila
dc.date.accessioned2024-06-12T19:59:42Z
dc.date.available2024-06-12T19:59:42Z
dc.date.issued2024-03-01
dc.description.abstractSerotonin (5-HT) is a neurotransmitter and neuromodulator that plays an essential role in physiological functions such as sleep, feeding, sexual behavior, temperature regulation, pain, and cognition. Also, it is involved in pathological states, including psychosis, pain management, mood and anxiety disorders. In the Central Nervous System (CNS), 5-HT acts through 14 different receptors once released by serotonergic neurons. These neurons belong in the midbrain Raphe nucleus and innervate many brain areas. Several studies have pointed out a role for serotonin in the reward system. Serotonergic projection neurons arising from dorsal and median Raphe nuclei innervate limbic brain areas involved in this system, such as the prefrontal cortex (PFC), ventral tegmental area (VTA), and nucleus accumbens (NAc), making the serotonergic system a modulator of synaptic transmission within mesocorticolimbic related areas. In PFC, this modulation is given by the activation of the 5-HT2A receptor (a G Coupled-Protein Receptor) that upon activation can produce increases in calcium and diacylglycerol intracellular levels, enhancing excitability and mediating endocannabinoid synthesis and release. In this regard, little is known about the serotonergic transmission in the NAc, where at least 6 types of 5-HT receptors (5-HT1A, 1B, 2C, 2A, and 4, 6) are expressed. In this nucleus, GABAergic medium spiny neurons (MSNs) comprise more than 90% of the neural population, but how serotonergic neurons modulate their activity is poorly understood when it comes to inhibitory transmission. To assess this question, we hypothesized that 5-HT modulates inhibitory transmission in the NAc core mainly through the activation of 5-HT2A receptor. Using a combination of electrophysiological and pharmacological techniques, such as whole-cell patch clamp, we evaluated evoked and spontaneous inhibitory transmission under the effect of different drugs. We discovered that 5-HT2A R activation produces a depression of the inhibitory synaptic transmission, also called iLTD (inhibitory long-term depression), that requires intracellular calcium rise upon GPCR activation (Gq), activation of PLCβ enzyme to form diacylglycerol (DAG) and inositol-1,4,5-triphosphate (IP3) and involves the production of endocannabinoids (e.g. 2-arachidonoylglycerol (2-AG)). 2-AG retrogradely decrease the release probability of GABA by the activation of presynaptic CB1 receptors. Therefore, acting in a pre and post-synaptic manner. This effect could be translated into an altered excitation/inhibition balance, which relates directly with the neurophysiological processes that underlie neuropsychiatric disorders such as addiction, schizophrenia and depression.
dc.description.sponsorshipThis thesis was funded by the Centro de Neurobiología y Fisiología Integrativa (CENFI - UV) through DIUV-CI Grant Nº 01/2006 (to MF and RS-Z) and The National Fund for Scientific and Technological Development (FONDECYT) Grants N° 112-2017 (to MF) and Nº 120–0474 (to RS-Z). Partial support was also received from PUENTE UVA 20993 (to MF). Finally, I was recipient of the doctorate fellowship N° 21180628 from “Agencia Nacional de Investigación y Desarrollo (ANID)”.
dc.facultadFacultad de Ciencias
dc.identifier.urihttps://repositoriobibliotecas.uv.cl/handle/uvscl/14007
dc.language.isoen
dc.publisherUniversidad de Valparaíso
dc.subjectSEROTONINA
dc.subjectSINAPSIS
dc.titleModulation of synaptic transmission in nucleus accumbens core by the activation of 5-HT₂ᴀ receptor in male mice
dc.typeThesis
uv.catalogadorPJR CIEN
uv.colectionTesis
uv.departamentoFacultad de Ciencias. Programa de Doctorado en Ciencias Mención en Neurociencia
uv.notageneralDoctor en Ciencias con Mención en Neurociencia. Universidad de Valparaíso. 2024.

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