RESUMEN
Depression is associated with dysregulated circadian rhythms, but the role of intrinsic clocks in mood-controlling brain regions remains poorly understood. We found increased circadian negative loop and decreased positive clock regulators expression in the medial prefrontal cortex (mPFC) of a mouse model of depression, and a subsequent clock countermodulation by the rapid antidepressant ketamine. Selective Bmal1KO in CaMK2a excitatory neurons revealed that the functional mPFC clock is an essential factor for the development of a depression-like phenotype and ketamine effects. Per2 silencing in mPFC produced antidepressant-like effects, while REV-ERB agonism enhanced the depression-like phenotype and suppressed ketamine action. Pharmacological potentiation of clock positive modulator ROR elicited antidepressant-like effects, upregulating plasticity protein Homer1a, synaptic AMPA receptors expression and plasticity-related slow wave activity specifically in the mPFC. Our data demonstrate a critical role for mPFC molecular clock in regulating depression-like behavior and the therapeutic potential of clock pharmacological manipulations influencing glutamatergic-dependent plasticity.
Asunto(s)
Factores de Transcripción ARNTL , Antidepresivos , Depresión , Ketamina , Ratones Noqueados , Corteza Prefrontal , Animales , Corteza Prefrontal/metabolismo , Corteza Prefrontal/efectos de los fármacos , Depresión/tratamiento farmacológico , Depresión/metabolismo , Depresión/genética , Ratones , Antidepresivos/farmacología , Masculino , Ketamina/farmacología , Factores de Transcripción ARNTL/metabolismo , Factores de Transcripción ARNTL/genética , Ritmo Circadiano/efectos de los fármacos , Ratones Endogámicos C57BL , Proteínas Circadianas Period/metabolismo , Proteínas Circadianas Period/genética , Modelos Animales de Enfermedad , Fenotipo , Plasticidad Neuronal/efectos de los fármacos , Receptores AMPA/metabolismo , Receptores AMPA/genética , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/metabolismo , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/genética , Proteínas de Andamiaje Homer/metabolismo , Proteínas de Andamiaje Homer/genética , Neuronas/metabolismo , Neuronas/efectos de los fármacosRESUMEN
Food intake, which is a highly reinforcing behavior, provides nutrients required for survival in all animals. However, when fat and sugar consumption goes beyond the daily needs, it can favor obesity. The prevalence and severity of this health problem has been increasing with time. Besides covering nutrient and energy needs, food and in particular its highly palatable components, such as fats, also induce feelings of joy and pleasure. Experimental evidence supports a role of the striatal complex and of the mesolimbic dopamine system in both feeding and food-related reward processing, with the nucleus accumbens as a key target for reward or reinforcing-associated signaling during food intake behavior. In this review, we provide insights concerning the impact of feeding, including fat intake, on different types of receptors and neurotransmitters present in the striatal complex. Reciprocally, we also cover the evidence for a modulation of palatable food intake by different neurochemical systems in the striatal complex and in particular the nucleus accumbens, with a focus on dopamine, GABA and the opioid system.
Asunto(s)
Analgésicos Opioides , Dopamina , Analgésicos Opioides/farmacología , Animales , Dopamina/farmacología , Ingestión de Alimentos , Conducta Alimentaria , Núcleo Accumbens , Recompensa , Ácido gamma-AminobutíricoRESUMEN
Recent studies have shown that cannabidiol (CBD) could have a great therapeutic potential for treating disorders such as chronic pain and anxiety. In the target article, the authors propose that CBD modulates serotonergic transmission and reverses allodynia and anxiety-like behaviour in a rat model of neuropathic pain. Furthermore, this study shows an antinociceptive effect mediated by TRPV1 and partially by 5-HT1A receptors, as well as an anxiolytic effect mediated by 5-HT1A receptors. Commentary on: De Gregorio D, McLaughlin RJ, Posa L, Ochoa-Sanchez R, Enns J, Lopez-Canul M, Aboud M, Maione S, Comai S, and Gobbi G. Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. PAIN 2019;160:36-150.