ORIGINAL INVESTIGATION Social stress-escalated intermittent alcohol drinking: modulation by CRF-R1 in the ventral tegmental area and accumbal dopamine in mice Lara S. Hwa 1 & Elizabeth N. Holly 1 & Joseph F. DeBold 1 & Klaus A. Miczek 1,2 Received: 12 September 2015 /Accepted: 29 October 2015 # Springer-Verlag Berlin Heidelberg 2015 Abstract Rationale Excessive alcohol (EtOH) drinking is difficult to model in animals despite the extensive human literature dem- onstrating that stress increases EtOH consumption. Objective The current experiments show escalations in volun- tary EtOH drinking caused by a history of social defeat stress and intermittent access to EtOH in C57BL/6J mice compared to non-stressed mice given intermittent EtOH or continuous EtOH. To explore a mechanistic link between stress and drink- ing, we studied the role of corticotropin-releasing factor type- 1 receptors (CRF-R1) in the dopamine-rich ventral tegmental area (VTA). Results Intra-VTA infusions of a CRF-R1 antagonist, CP376395, infused into the VTA dose-dependently and selec- tively reduced intermittent EtOH intake in stressed and non- stressed mice, but not in mice given continuous EtOH. In contrast, intra-VTA infusions of the CRF-R2 antagonist astressin2B non-specifically suppressed both EtOH and H 2 O drinking in the stressed group without effects in the non- stressed mice. Using in vivo microdialysis in the nucleus ac- cumbens (NAc) shell, we observed that stressed mice drinking EtOH intermittently had elevated levels of tonic dopamine concentrations compared to non-stressed drinking mice. Also, VTA CP376395 potentiated dopamine output to the NAc only in the stressed group causing further elevations of dopamine post-infusion. Conclusions These findings illustrate a role for extrahypothalamic CRF-R1 as especially important for stress-escalated EtOH drinking beyond schedule-escalated EtOH drinking. CRF-R1 may be a mechanism for balancing the dysregulation of stress and reward in alcohol use disorders. Keywords Alcohol . Intermittent . Social defeat stress . Ventral tegmental area . CRF-R1 . CRF-R2 . Dopamine . Nucleus accumbens . Microdialysis Introduction The anxiolytic, stress-relieving effects of EtOH are well established in humans and animal models, as the tension re- duction hypothesis remains one of the oldest theories for why individuals consume EtOH (Conger 1956). There have been many experimental methods to increase EtOH drinking in animals, but not all generate stress-enhanced consumption (Becker et al. 2011). Social defeat and subordination stress can lead to increased EtOH drinking in mice and monkeys compared to non-stressed animals or higher ranking individ- uals (Sillaber et al. 2002; Peretti and Lewis 1969; but see Van Erp and Miczek 2001). We recently explored specific defeat stress parameters that escalated two-bottle-choice EtOH drinking in outbred mice (Norman et al. 2015). This 10-day episodic defeat caused chronic elevations in corticosterone (Norman et al. 2015), indicative of altered hypothalamic- pituitary-adrenal (HPA) stress function. This cascade of endo- crine stress responses is initiated by corticotropin-releasing factor (CRF), coordinating behavioral responses in socially defeated animals (Heinrichs et al. 1992). Not only is CRF integral to social defeat stress, the neuro- peptide has also been implicated in heavy EtOH drinking. CRF receptor type-1 (CRF-R1) antagonists have been used * Klaus A. Miczek klaus.miczek@tufts.edu 1 Psychology Department, Tufts University, 530 Boston Avenue, Medford, MA 02155, USA 2 Neuroscience Department, Tufts University, Boston, MA 02111, USA Psychopharmacology DOI 10.1007/s00213-015-4144-2