RESUMEN
The adolescent brain displays high vulnerability to the deleterious effects of ethanol, including greater risk of developing alcohol use disorder later in life. Here, we characterized the gene expression of the endocannabinoid system (ECS) and relevant signaling systems associated with neuroinflammation and emotional behaviors in the brain of young adult control and ethanol-exposed (EtOH) rats. We measured mRNA levels of candidate genes using quantitative real time PCR in the medial prefrontal cortex (mPFC), amygdala and hippocampus. EtOH rats were generated by maintenance on an intermittent and voluntary ethanol consumption during adolescence using the two-bottle choice paradigm (4 days/week for 4 weeks) followed by 2 week-withdrawal, a time-point of withdrawal with no physical symptoms. Mean differences and effect sizes were calculated using t-test and Cohen's d values. In the mPFC and hippocampus, EtOH rats had significantly higher mRNA expression of endocannabinoid-signaling (mPFC: Ppara, Dagla, Daglb and Napepld; and hippocampus: Cnr2, Dagla and Mgll) and neuroinflammation-associated genes (mPFC: Gfap; and hippocampus: Aif1) than in controls. Moreover, EtOH rats had significantly higher mRNA expression of neuropeptide Y receptor genes (Npy1r, Npy2r and Npy5r) in the hippocampus. Finally, EtOH rats also displayed higher plasma endocannabinoid levels than controls. In conclusion, these results suggest that adolescent ethanol exposure can lead to long-term alterations in the gene expression of the ECS and other signaling systems involved in neuroinflammation and regulation of emotional behaviors in key brain areas for the development of addiction.
Asunto(s)
Consumo de Bebidas Alcohólicas/efectos adversos , Depresores del Sistema Nervioso Central/efectos adversos , Endocannabinoides/genética , Endocannabinoides/metabolismo , Etanol/efectos adversos , Mediadores de Inflamación/metabolismo , Animales , Ansiedad/psicología , Emociones , Expresión Génica/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Psicología del Adolescente , Desempeño Psicomotor/efectos de los fármacos , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Wistar , Receptores de Neuropéptido Y/efectos de los fármacos , Receptores de Neuropéptido Y/genética , Receptores de Neuropéptido Y/metabolismoRESUMEN
The LPA1 receptor, one of the six characterized G protein-coupled receptors (LPA1-6) through which lysophosphatidic acid acts, is likely involved in promoting normal emotional behaviours. Current data suggest that the LPA-LPA1-receptor pathway may be involved in mediating the negative consequences of stress on hippocampal function. However, to date, there is no available information regarding the mechanisms whereby the LPA1 receptor mediates this adaptation. To gain further insight into how the LPA-LPA1 pathway may prevent the negative consequences of chronic stress, we assessed the effects of the continuous delivery of LPA on depressive-like behaviours induced by a chronic restraint stress protocol. Because a proper excitatory/inhibitory balance seems to be key for controlling the stress response system, the gene expression of molecular markers of excitatory and inhibitory neurotransmission was also determined. In addition, the hippocampal expression of mineralocorticoid receptor genes and glucocorticoid receptor genes and proteins as well as plasma corticosterone levels were determined. Contrary to our expectations, the continuous delivery of LPA in chronically stressed animals potentiated rather than inhibited some (e.g., anhedonia, reduced latency to the first immobility period), though not all, behavioural effects of stress. Furthermore, this treatment led to an alteration in the genes coding for proteins involved in the excitatory/inhibitory balance in the ventral hippocampus and to changes in corticosterone levels. In conclusion, the results of this study reinforce the assumption that LPA is involved in emotional regulation, mainly through the LPA1 receptor, and regulates the effects of stress on hippocampal gene expression and hippocampus-dependent behaviour.
Asunto(s)
Conducta Animal , Hipocampo/fisiopatología , Receptores del Ácido Lisofosfatídico/genética , Estrés Psicológico/genética , Estrés Psicológico/psicología , Anhedonia , Animales , Enfermedad Crónica , Corticosterona/sangre , Depresión/psicología , Expresión Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Inhibición Neural , Receptores de Mineralocorticoides/biosíntesis , Receptores de Mineralocorticoides/genética , Estrés Psicológico/fisiopatología , Natación/psicología , Transmisión SinápticaRESUMEN
BACKGROUND AND PURPOSE: Lipogenesis is intimately controlled by hormones and cytokines as well as nutritional conditions. IL-6 participates in the regulation of fatty acid metabolism in the liver. We investigated the role of IL-6 in mediating fasting/re-feeding changes in the expression of hepatic lipogenic enzymes. EXPERIMENTAL APPROACH: Gene and protein expression of lipogenic enzymes were examined in livers of wild-type (WT) and IL-6-deficient (IL-6(-/-) ) mice during fasting and re-feeding conditions. Effects of exogenous IL-6 administration on gene expression of these enzymes were evaluated in vivo. The involvement of STAT3 in mediating these IL-6 responses was investigated by using siRNA in human HepG2 cells. KEY RESULTS: During feeding, the up-regulation in the hepatic expression of lipogenic genes presented similar time kinetics in WT and IL-6(-/-) mice. During fasting, expression of lipogenic genes decreased gradually over time in both strains, although the initial drop was more marked in IL-6(-/-) mice. Protein levels of hepatic lipogenic enzymes were lower in IL-6(-/-) than in WT mice at the end of the fasting period. In WT, circulating IL-6 levels paralleled gene expression of hepatic lipogenic enzymes. IL-6 administration in vivo and in vitro showed that IL-6-mediated signalling was associated with the up-regulation of hepatic lipogenic enzyme genes. Moreover, silencing STAT3 in HepG2 cells attenuated IL-6 mediated up-regulation of lipogenic gene transcription levels. CONCLUSIONS AND IMPLICATIONS: IL-6 sustains levels of hepatic lipogenic enzymes during fasting through activation of STAT3. Our findings indicate that clinical use of STAT3-associated signalling cytokines, particularly against steatosis, should be undertaken with caution.
Asunto(s)
Ayuno/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Interleucina-6/farmacología , Hígado/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Acetil-CoA Carboxilasa/genética , Acetil-CoA Carboxilasa/metabolismo , Animales , Acido Graso Sintasa Tipo I/genética , Acido Graso Sintasa Tipo I/metabolismo , Células Hep G2 , Humanos , Interleucina-6/sangre , Interleucina-6/genética , Lipogénesis/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Recombinantes/farmacología , Estearoil-CoA Desaturasa/genética , Estearoil-CoA Desaturasa/metabolismoRESUMEN
By inbreeding we have obtained two sublines of Sprague-Dawley rats which differ significantly in spontaneous mean yawning frequency (MYF). In generation F21 of the high-yawning (HY) subline MYF was 21.5 yawns/h (y/h) in males and 1.95 y/h in females, at the age of 2 months. In the low-yawning (LY) subline, in generation F16 the MYF was 0.9 y/h in males and only 0.5 y/h in females. During the first 15 days there are no differences in yawning frequency between HY and LY rats. Thereafter yawning increases with age, more steeply in the HY subline. The results of reciprocal crosses between both sublines indicate that the LY character is partially dominant over the HY one.