The recreational drugs, alcohol and 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") have both been shown to cause immune activation in vivo, and they are linked to cognitive impairment and anxiety-like behaviors in rodents. The neuronal effects of these drugs in the hippocampal area, an area that has been a focus of studies aiming to explain the mechanisms underlying anxiety related-disorders, remains poorly understood. Therefore we investigated the specific inflammatory impact of alcohol and MDMA on this area of the brain and on a hippocampal-related behavioral task. We centered our study on two inflammatory factors linked to anxiety-related disorders, namely Interleukin-1β (IL-1β) and brain-derived neurotrophic factor (BDNF). We subjected drug-consuming mice to a battery of behavioral tests to evaluate general activity, anxiety-like and depressive-live behaviors. We then introduced them to a contextual fear discrimination task and immune-related effects were examined by immunohistochemical and biochemical studies. Our results suggest that there is a relationship between the induction of immune activated pathways by voluntary alcohol consumption and a high-dose MDMA. Furthermore, the ability of mice to perform a contextual fear discrimination task was impaired by drug consumption and we report long term inflammatory alterations in the hippocampus even several weeks after drug intake. This information will be helpful for discovering new selective drug targets, and to develop treatments and preventive approaches for patients with anxiety-related disorders.

This study was supported by Ministery of Economy (SAF2013-41761-R-FEDER), Ministery of Health (Retic-ISCIII-FEDER-RD12/0028/0024- and Plan Nacional sobre Drogas - 2014/020), and Generalitat de Catalunya (2014SGR34) to Olga Valverde; and Ministery of Health (Retic-ISCIIIFEDER-RD06/0001/1004, RD12/0028/0019) to Jorge Manzanares. Emily Johansson was a recipient of a fellowship from Stiftelsen Olle Engkvist Byggmästare and Bodil Torkelssons stiftelse.

The study was supported by Instituto de Salud Carlos III [ISCIII; FIS PI11/00210, FIS PI14/ 00290 and Ministerio de de Economía y Competitividad (PSI2011-28349)] and co-funded by Fondos Europeos de Desarrollo Regional (FEDER) funds - a way to build Europe. José C. FernándezGarcía is the recipient of a research contract from Servicio Andaluz de Salud (SAS) (B-0033-2014). CIBERobn and CIBERSAM are both initiatives of ISCIII.