Deletion of Dlk1 increases the vulnerability to developing anxiety-like behaviors and ethanol consumption in mice

Anxiety and alcohol use disorders (AUD) often present together, constituting a significant public health problem worldwide. In this study, we investigated the role of DLK1, a ligand of the Delta/NOTCH epidermal growth factor (EGF)-like protein family, reported to play a role in DA neurons differentiation in the striatum, as a neurobiological factor involved in the mechanisms regulating this psychiatric comorbidity. We exposed Dlk1 knockout mice (Dlk1−/− mice) to the open-field (OF), the light-dark box (LBD) and the elevated plus maze (EPM) tests, evaluating motivation to drink and ethanol consumption using the oral ethanol self-administration (OEA) paradigm. Quantitative real time polymerase chain reaction (qPCR) studies were carried out to evaluate alterations in targets closely related to DA neurotransmission in the reward system, tyrosine hydroxylase (Th) in the ventral tegmental area (VTA), and μ-opioid receptor (Oprm1) in the nucleus accumbens (NAc). No differences were observed in the total or peripheral distances travelled by Dlk1−/− compared to wild-type (WT) mice in OF. However, central distance travelled significantly decreased in Dlk1−/− mice. Deletion of Dlk1 increased anxiety-like behaviors in the LDB and EPM, and, Dlk1−/− mice also presented higher ethanol intake and motivation to drink (number of effective responses) in the OEA. In addition, Th and Oprm1 gene expression was reduced in the VTA and NAc of Dlk1−/− mice. We conclude that deletion of Dlk1 increases anxiety-related behaviors and vulnerability to ethanol consumption and modifies the gene expression of key targets closely related with DA neurotransmission involved in the reinforcing actions of ethanol.
This research was supported by Health Institute Carlos III (Retics, RD16/0017/0014), National Plan on Drug Abuse (PNSD 2016/016) and the Spanish Ministry of Economics and Competitivity (FIS, PI14/00438) to JM, and by Department of Education, Culture and Sports (European Regional Development Fund, Council of Communities of Castilla la Mancha, Spain (PEII-2014-033-P) to JL.