RESUMEN
Exposure to repeated social stress may cause maladaptive emotional reactions that can be reduced by healthy nutritional supplementation. Histaminergic neurotransmission has a central role in orchestrating specific behavioural responses depending on the homeostatic state of a subject, but it remains to be established if it participates in the protective effects against the insults of chronic stress afforded by a healthy diet. By using C57BL/6J male mice that do not synthesize histamine (Hdc-/-) and their wild type (Hdc+/+) congeners we evaluated if the histaminergic system participates in the protective action of a diet enriched with polyunsaturated fatty acids and vitamin A on the deleterious effect of chronic stress. Behavioural tests across domains relevant to cognition and anxiety were performed. Hippocampal synaptic plasticity, cytokine expression, hippocampal fatty acids, oxylipins and microbiota composition were also assessed. Chronic stress induced social avoidance, poor recognition memory, affected hippocampal long-term potentiation, changed the microbiota profile, brain cytokines, fatty acid and oxylipins composition of both Hdc-/- and Hdc+/+ mice. Dietary enrichment counteracted stress-induced deficits only in Hdc+/+ mice as histamine deficiency prevented almost all the diet-related beneficial effects. Interpretation: Our results reveal a previously unexplored and novel role for brain histamine as a mediator of many favorable effects of the enriched diet. These data present long-reaching perspectives in the field of nutritional neuropsychopharmacology.
Asunto(s)
Dieta , Disbiosis , Microbioma Gastrointestinal , Histamina/metabolismo , Conducta Social , Estrés Psicológico , Animales , Conducta Animal , Biomarcadores , Peso Corporal , Citocinas/metabolismo , Ácidos Grasos/metabolismo , Expresión Génica , Hipocampo/metabolismo , Hipocampo/fisiopatología , Locomoción , Masculino , Metagenoma , Metagenómica , Ratones , Ratones Noqueados , Modelos AnimalesRESUMEN
Trazodone is an antidepressant drug with considerable affinity for 5-HT1A receptors and α1-adrenoceptors for which the drug is competitive agonist and antagonist, respectively. In this study, we used cell-attached or whole-cell patch-clamp recordings to characterize the effects of trazodone at somatodendritic 5-HT1A receptors (5-HT1AARs) and α1-adrenoceptors of serotonergic neurons in rodent dorsal raphe slices. To reveal the effects of trazodone at α1-adrenoceptors, the baseline firing of 5-HT neurons was facilitated by applying the selective α1-adrenoceptor agonist phenylephrine at various concentrations. In the absence of phenylephrine, trazodone (1-10 µM) concentration-dependently silenced neurons through activation of 5-HT1AARs. The effect was fully antagonized by the selective 5-HT1A receptor antagonist Way-100635. With 5-HT1A receptors blocked by Way-100635, trazodone (1-10 µM) concentration-dependently inhibited neuron firing facilitated by 1 µM phenylephrine. Parallel rightward shift of dose-response curves for trazodone recorded in higher phenylephrine concentrations (10-100 µM) indicated competitive antagonism at α1-adrenoceptors. Both effects of trazodone were also observed in slices from Tph2-/- mice that lack synthesis of brain serotonin, showing that the activation of 5-HT1AARs was not mediated by endogenous serotonin. In whole-cell recordings, trazodone activated 5-HT1AAR-coupled G protein-activated inwardly-rectifying (GIRK) channel conductance with weak partial agonist efficacy (~35%) compared to that of the full agonist 5-CT. Collectively our data show that trazodone, at concentrations relevant to its clinical effects, exerts weak partial agonism at 5-HT1AARs and disfacilitation of firing through α1-adrenoceptor antagonism. These two actions converge in inhibiting dorsal raphe serotonergic neuron activity, albeit with varying contribution depending on the intensity of α1-adrenoceptor stimulation.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Antidepresivos/farmacología , Núcleo Dorsal del Rafe/efectos de los fármacos , Neuronas Serotoninérgicas/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Trazodona/farmacología , Animales , Núcleo Dorsal del Rafe/citología , Núcleo Dorsal del Rafe/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Noqueados , Técnicas de Placa-Clamp , Fenilefrina/farmacología , Piperazinas/farmacología , Piridinas/farmacología , Ratas , Receptor de Serotonina 5-HT1A/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Neuronas Serotoninérgicas/metabolismo , Triptófano Hidroxilasa/genéticaRESUMEN
Brain serotonin (5-hydroxytryptamine, 5-HT) system dysfunction is implicated in exaggerated fear responses triggering various anxiety-, stress-, and trauma-related disorders. However, the underlying mechanisms are not well understood. Here, we investigated the impact of constitutively inactivated 5-HT synthesis on context-dependent fear learning and extinction using tryptophan hydroxylase 2 (Tph2) knockout mice. Fear conditioning and context-dependent fear memory extinction paradigms were combined with c-Fos imaging and electrophysiological recordings in the dorsal hippocampus (dHip). Tph2 mutant mice, completely devoid of 5-HT synthesis in brain, displayed accelerated fear memory formation and increased locomotor responses to foot shock. Furthermore, recall of context-dependent fear memory was increased. The behavioral responses were associated with increased c-Fos expression in the dHip and resistance to foot shock-induced impairment of hippocampal long-term potentiation (LTP). In conclusion, increased context-dependent fear memory resulting from brain 5-HT deficiency involves dysfunction of the hippocampal circuitry controlling contextual representation of fear-related behavioral responses.