RESUMEN
Behavioral and clinical studies suggest a critical role of substance P (SP)/neurokinin-1 receptor (NK-1R) signaling in alcohol dependence. Here, we examined regulation of GABA transmission in the medial subdivision of the central amygdala (CeM) by the SP/NK-1R system, and its neuroadaptation following chronic alcohol exposure. In naïve rats, SP increased action potential-dependent GABA release, and the selective NK-1R antagonist L822429 decreased it, demonstrating SP regulation of CeM activity under basal conditions. SP induced a larger GABA release in alcohol-dependent rats accompanied by decreased NK-1R expression compared to naïve controls, suggesting NK-1R hypersensitivity which persisted during protracted alcohol withdrawal. The NK-1R antagonist blocked acute alcohol-induced GABA release in alcohol-dependent and withdrawn but not in naïve rats, indicating that dependence engages the SP/NK-1R system to mediate acute effects of alcohol. Collectively, we report long-lasting CeA NK-1R hypersensitivity corroborating that NK-1Rs are promising targets for the treatment of alcohol use disorder.
Asunto(s)
Alcoholismo/etiología , Alcoholismo/metabolismo , Núcleo Amigdalino Central/metabolismo , Receptores de Neuroquinina-1/agonistas , Receptores de Neuroquinina-1/metabolismo , Transducción de Señal/efectos de los fármacos , Sustancia P/metabolismo , Adaptación Fisiológica , Animales , Núcleo Amigdalino Central/fisiopatología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Expresión Génica , Inmunohistoquímica , Masculino , Ratas , Receptores de Neuroquinina-1/genética , Síndrome de Abstinencia a Sustancias , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Aberrant serotonergic neurotransmission in the brain is considered at the core of the pathophysiological mechanisms involved in neuropsychiatric disorders. Gene by environment interactions contribute to the development of depression and involve modulation of the availability and functional activity of the serotonin transporter (SERT). Using behavioral and in vivo electrophysiological approaches together with biochemical, molecular-biological and molecular imaging tools we establish Flotillin-1 (Flot1) as a novel protein interacting with SERT and demonstrate its involvement in the response to chronic corticosterone (CORT) treatment. We show that genetic Flot1 depletion augments chronic CORT-induced behavioral despair and describe concomitant alterations in the expression of SERT, activity of serotonergic neurons and alterations of the glucocorticoid receptor transport machinery. Hence, we propose a role for Flot1 as modulatory factor for the depressogenic consequences of chronic CORT exposure and suggest Flotillin-1-dependent regulation of SERT expression and activity of serotonergic neurotransmission at the core of the molecular mechanisms involved.
Asunto(s)
Corticosterona/metabolismo , Depresión/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Animales , Femenino , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Unión Proteica , Neuronas Serotoninérgicas/metabolismoRESUMEN
Impairment of hand dexterity in Parkinson's disease (PD) is usually attributed to bradykinesia. Recently, behavioral studies illustrated that decreased dexterity might also be due to limb-kinetic apraxia (LkA), as demonstrated by impaired performance in a coin rotation task. Here, we provide a first investigation on whether functional magnetic resonance imaging (fMRI) may reveal specific brain activation patterns for PD patients with impaired performance in a coin rotation task. We compared coin rotation as an apraxia task to simple finger tapping as a bradykinesia task in ten PD patients OFF medication and matched healthy controls. In addition to a tendency for general overactivation, PD patients showed a perirolandic dissociation with precentral overactivation and postcentral underactivation. This finding significantly separated PD patients from healthy controls.
