To investigate the impact of repeated cocaine on stress vulnerability, we utilized a submaximal version of social defeat. Previous work has shown that 10 days of defeat stress induces several cardinal depressive-like behaviors, such as social avoidance and reduced sucrose preference (Berton et al., 2006 and Krishnan et al., 2007). Here, only 8 days of defeat stress were used, which in initial studies DAPT in vivo did not induce these symptoms. Next, either saline or a sensitizing regimen

of cocaine was administered prior to initiating 8 days of defeat stress (Figure 1A). Seven days of repeated cocaine (20 mg/kg/day), immediately followed by 8 days of defeat stress, revealed social avoidance (Figure 1B) and diminished sucrose preference (Figure 1D). This is

in contrast to control animals receiving saline prior to chronic stress, which showed no such deleterious behavioral responses. To further verify the potential long-lasting effects of cocaine on behavioral deficits observed after 8 days of defeat stress, RAD001 molecular weight animals were re-exposed to a low dose of cocaine (5 mg/kg) 24 hr after the social interaction test (see Figure S1A available online). Both stressed and nonstressed cocaine-treated animals displayed sensitized locomotor responses to cocaine. The social stress did not, however, potentiate cocaine-induced locomotor activity in cocaine-naive mice (Figure S1B). Animals exposed to cocaine, in the absence of later social stress, displayed more rapid social interaction (i.e., decreased

latency to interact)—an effect of cocaine that was completely reversed by exposure to 8 days of defeat stress (Figure 1C). The effects of cocaine, stress, or the combination of both stimuli had no impact on general levels of locomotor activity (Figure 1E). Cocaine, when self-administered during binges, increases thresholds for intracranial self-stimulation, indicating a withdrawal syndrome characterized by anhedonia (Markou and Koob, 1991). However, as shown in Figures 1B and Non-specific serine/threonine protein kinase 1D, we did not observe an effect of cocaine alone on social interaction or sucrose preference. We have shown recently that, following repeated (not acute) cocaine, the repressive histone modification, H3K9me2, and its associated “writer” enzymes, G9a and GLP, are reduced in NAc, leading to the activation of numerous synaptic plasticity-related transcripts, increased dendritic spine density on medium spiny neurons (MSNs), and enhanced cocaine reward (Maze et al., 2010). To validate these earlier findings, animals were treated with either saline or cocaine (20 mg/kg/day) for 7 days. At 24 hr after the final injection, NAc dissections were collected and analyzed for global alterations in G9a and H3K9me2 expression. Consistent with previous data, levels of G9a mRNA (saline versus repeated cocaine, t10 = 2.559; p < 0.