Timing of SCH23390 Administration Influences Extinction of Conditioned Hyperactivity in Mice Anthony S. Rauhut 1,2, Kristen Ratner2, Sandy Buck2, and Ee-Rah Sung2 Department of Psychology1 and Neuroscience Program2, Dickinson College Results Introduction Drug addiction has been conceptualized as a disorder of memory (Hyman, 2005). Recently, authors have linked drug addiction with other memory disorders (e.g., post-traumatic stress disorder), suggesting that these disorders stem from prefrontal cortical pathology, contributing to impaired extinction processes (Peters et al., 2009). Moreover, pharmacologically targeting extinction processes has been proposed as a novel therapeutic treatment for drug addiction in people (Taylor et al., 2009). The dopaminergic system has been implicated in mediating extinction-related processes (e.g., memory reconsolidation) as assessed in both aversive and appetitive Pavlovian conditioning paradigms (for a recent review see Abraham et al., 2014). In addition, many studies, using the highly selective dopamine subtype-1 (D1) receptor antagonist, SCH 23390, have specifically linked the D1 receptor to memory reconsolidation. For example, injections of SCH 23390 immediately following extinction sessions retards the rate of extinction in the auditory fear conditioning (Hikind and Maroun, 2008) and cocaine-produced conditioned place preference (Fricks-Gleason et al., 2012) paradigms. Swiss Webster Mouse Locomotor Activity Chamber Methods Figure 1. Mean distance traveled (cm) for paired and unpaired mice during the acquisition (Top Panel) or extinction (Bottom Panel) phases of Experiment 1. SCH 23390 doses (vehicle, 0.0125, 0.025 or 0.05 mg/kg) were administered (IP) immediately after each extinction session. Error bars represent the + 1 SEM. (*) = significant difference between paired and unpaired mice collapsed across dose; (#) = significant difference between Chamber Days 1 and 4 for paired mice collapsed across dose. All ps < .05. Acclimation (14 days) Conditioning (8 days) Paired Meth + Chamber (4 days) Saline + Home Cage (4 days) Unpaired Saline + Chamber (4 days) Meth + Home Cage (4 days) Extinction (5 - 7 days) All mice receive an injection (SC) of vehicle before placement in locomotor activity chambers. Injection of SCH22930 (IP) Vehicle Saline (n = 6) Low Dose 0.0125 mg/kg (n = 8) Moderate Dose 0.025 mg/kg High Dose 0.05 mg/kg 24 h Methamphetamine SCH 23390 Purpose/Prediction Injection SCH23390 0.05 mg/kg or vehicle prior to extinction (Experiment 2) 48 hours later (Experiment 2) While previous studies have substantiated a role for the D1 receptor in memory reconsolidation, no studies have utilized the conditioned hyperactivity paradigm. To this end, Experiment 1 examined the effects of various doses of SCH 23390, when administered immediately after the extinction sessions, on memory reconsolidation, as measured by the rate of extinction of conditioned hyperactivity. A control experiment (Experiment 2) examined the effects of SCH 23390 administered prior to extinction sessions on retrieval (or expression) of conditioned hyperactivity in mice, as it has been shown that SCH 23390 administered prior to an extinction test blunts expression of conditioned hyperactivity in rats (Drew and Glick, 1990). Figure 2. Mean distance traveled (cm) for paired and unpaired mice during the extinction phase of Experiment 2. SCH 23390 doses (vehicle or 0.05 mg/kg) were administered (IP) 30 minutes before each extinction session. Error bars represent the + 1 SEM. (*) = significant difference between paired + vehicle mice and unpaired + vehicle mice. (&) = significant difference between paired + SCH 23390 mice and paired + vehicle mice. All ps < .05. Discussion Methamphetamine produced behavioral sensitization followed by robust conditioned hyperactivity in mice, consistent with previous work in the laboratory (Rauhut and Bialecki, 2011; White and Rauhut, 2014). Repeated exposures of the chamber in the absence of methamphetamine weakened conditioned hyperactivity (i.e., extinction), consistent with another conditioned hyperactivity study (Drew and Glick, 1990). A key finding of Experiment 1 was that administration of SCH 23390, across a wide dose-response range, immediately following extinction sessions did not alter the rate of extinction in paired mice. This result is not consistent with other studies showing that immediate post-session administration of SCH 23390 disrupts memory consolidation and retards extinction (Hikind and Maroun, 2008; Fricks-Gleason et al., 2012). In Experiment 2, however, SCH 23390 administered at a dose (0.05 mg/kg) that did not disrupt memory reconsolidation or alter the rate of extinction in Experiment 1, blocked retrieval (or expression) of conditioned hyperactivity in mice when administered prior to daily extinction sessions. These results, when viewed in tandem with another recent study (Carrera et al., 2013), suggest that the D1 receptor plays a role in memory retrieval whereas the D2 receptor mediates memory reconsolidation during extinction of conditioned hyperactivity. Immediately after (Experiment 1) Acknowledgements This research was financially supported by the Psychology Department at Dickinson College.