RESUMEN
BACKGROUND: Data have shown a role of α-synuclein in anxiety and also in addiction, particularly in alcohol use disorders (AUD). Since the comorbidity between AUD and anxiety is very high and because anxiety is an important factor in ethanol (EtOH) relapse, the aim of the present study was to investigate the role of α-synuclein in moderating EtOH intake, the anxiolytic effects of EtOH, and EtOH withdrawal-induced anxiety and convulsions in mice. The study aimed to determine whether SNCA variants moderated anxiety in EtOH-dependent patients. METHODS: We analyzed the moderator effect of 3 SNCA Tag-single nucleotide polymorphisms (Tag-SNPs) rs356200, rs356219, and rs2119787 on the anxiety symptoms in 128 EtOH-dependent patients. We used the C57BL/6JOlaHsd Snca mutant mice to assess EtOH intake; sensitivity to the anxiolytic effects of EtOH in a test battery comprising the open field, the light-dark box, and the elevated plus maze; and both anxiety and convulsions induced by EtOH withdrawal. RESULTS: Our results demonstrated a reduction in both EtOH intake and preference and also a lack of sensitivity to the anxiolytic effects of EtOH in α-synuclein mutant mice. Results on anxiety-like behavior were mixed, but mutant mice displayed increased anxiety when exposed to a low anxiogenic environment. Mutant mice also displayed an increase in handling-induced convulsion scores during withdrawal after EtOH inhalation, but did not differ in terms of EtOH withdrawal-induced anxiety. In humans, we found a significant association of the rs356219 SNP with a high level of anxiety (Beck Anxiety Inventory score >15) and the rs356200 SNP with a positive familial history of AUD. CONCLUSIONS: Our translational study highlights a significant role of α-synuclein in components of AUD.
Asunto(s)
Alcoholismo/genética , Alcoholismo/psicología , Ansiedad/genética , Ansiedad/psicología , Conducta Animal/efectos de los fármacos , Depresores del Sistema Nervioso Central/farmacología , Etanol/farmacología , alfa-Sinucleína/genética , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Actividad Motora/efectos de los fármacos , Mutación/genética , Pruebas Neuropsicológicas , Polimorfismo de Nucleótido Simple , Convulsiones/inducido químicamente , Convulsiones/psicología , Síndrome de Abstinencia a Sustancias/genética , Síndrome de Abstinencia a Sustancias/psicología , Adulto JovenRESUMEN
There is emerging evidence that the adenosinergic system might be involved in drug addiction and alcohol dependence. We have already demonstrated the involvement of A2A receptors (A2AR) in ethanol-related behaviours in mice. Here, we investigated whether the A2AR agonist CGS 21680 can reduce ethanol operant self-administration in both non-dependent and ethanol-dependent Wistar rats. To rule out a potential involvement of the A1R in the effects of CGS 21680, we also tested its effectiveness to reduce ethanol operant self-administration in both heterozygous and homozygous A1R knockout mice. Our results demonstrated that CGS 21680 (0.065, 0.095 and 0.125 mg/kg, i.p.) had a bimodal effect on 10% ethanol operant self-administration in non-dependent rats. The intermediate dose was also effective in reducing 2% sucrose self-administration. Interestingly, the intermediate dose reduced 10% ethanol self-administration in dependent animals more effectively (75% decrease) when compared with non-dependent animals (57% decrease). These results suggest that the A2AR are involved in CGS 21680 effects since the reduction of ethanol self-administration was not dependent upon the presence of A1R in mice. In conclusion, our findings demonstrated the effectiveness of the A2AR agonist CGS 21680 in a preclinical model of alcohol addiction and suggested that the adenosinergic pathway is a promising target to treat alcohol addiction.