Research supported by PHS grants DA06214 and DA017289.

1. Cocaine-induced elevations in FosB/∆FosB correlate with increased drug reward and decreased novelty reward. • S.D. Mague1, M. Wimmer1, G.C. Harris1 and G. Aston-Jones2 • 1.Neuroscience Graduate Program, University of Pennsylvania, Philadelphia, PA • 2. Department of Neurosciences, Medical University of South Carolina, Charleston, SC INTRODUCTION Only in the NAc-shell do FosB/∆FosB counts correlate with increased cocaine and decreased novelty preference following both 2 and 5 weeks of drug abstinence Cocaine withdrawn animals show an altered hedonic response to natural and drug rewards. Chronic cocaine treatment elevates FosB/∆FosB staining in the NAc-shell, NAc-core, and BLA. b. a. Rats treated chronically with morphine or cocaine show an increased preference for drug rewards, but a decreased preference for natural rewards1. ∆FosB accumulates in reward-related brain regions following chonic exposure to drugs of abuse2. It has been suggested that the stability of ∆FosB could explain the long-lasting effects of chronic drug exposure3. HYPOTHESIS: If ∆FosB accumulation is responsible for alterations in hedonic processing, then elevations in FosB/∆FosB in reward-related brain regions following chronic cocaine exposure should correlate with increases in acute cocaine preference and decreases in novel-object preference. Figure 2. Example of coronal brain sections stained for FosB/∆FosB in cocaine withdrawn (a) and saline animals (b). Rats were perfused 2 h after preference test in cocaine CPP. Ac: nucleus accumbens, BLA: basolateral amygdala, CE: central amygdala, LA: lateral amygdala. A B Figure 4. Correlation R values for FosB/∆FosB counts (NAc-shell, NAc-core, and BLA) and CPP scores in animals undergoing novel-object (red) or cocaine (blue) place-conditioning studies. n = 10-14. Only in the NAc-shell is FosB/∆FosB elevated following both 2 and 5 weeks of cocaine abstinence. a. b. Experimental Design CONCLUSIONS Cocaine exposure followed by 2 to 5 weeks of abstinence results in altered hedonic processing in which cocaine cues become more highly rewarding, and novel-object cues become less rewarding. FosB/∆FosB is elevated in several reward-related brain regions following 2-3 weeks of cocaine abstinence. However, only in the NAc-shell is FosB/∆FosB accumulation still elevated after 5 weeks of withdrawal. Increased cocaine preference and decreased novel-object preference after 5 weeks of drug abstinence correlate with elevated FosB/∆FosB counts only in the NAc-shell, suggesting that this brain region may be responsible for the alteration in hedonic processing. 10-day Coc 2-5 week abstinence Coc/Novelty CPP CPP Box Novel Objects Figure 1. Preference scores for the novel object-paired (a) or cocaine-paired (b) environment expressed as the mean time (in seconds) spent in the paired side minus the mean time spent on the non-paired side on the test day. *p<.01; n = 10-14. Cocaine Conditioning: Rats received an injection of cocaine (10 mg/kg i.p.) and were placed in one chamber for 30 min; 4 hours later they were injected with saline and placed in the other chamber. The order of pairings alternated daily. Animals were conditioned for 3 consecutive days. Novelty Conditioning: Rats were exposed to a novel object in one chamber for 10 min; 1 hour later they were exposed to the other chamber without an object. The order of pairings alternated daily for 8 days; a different object was used each day. Test Day: 24 hr following the final conditioning day, rats were tested for cocaine or novel-object preference by allowing free access to both chambers for a 15 min session. Animals were perfused 2 hr after this test session and tissue was prepared for FosB/∆FosB staining. For all experiments, male Sprague-Dawley rats 300-350g were used. Immunoreactivity: Coronal brain sections from animals in the above experiment were reacted with antibodies targeting the FosB/∆FosB protein (1:500, Santa Cruz Biotechnology, Inc), incubated with the secondary antibody (biotinylated goat anti-rabbit 1:500, Jackson Immunoresearch Laboratories, West Grove, PA) and an avidin biotin complex, and visualized with DAB and nickel ammonium sulfate. References Harris, G.C. & Aston-Jones, G. (2003) Neuropsychopharm28, 865-871. Chen, J.S., Zhang, Y.J., Kelz, M.B., Steffen, C., Ang, E.S., Zeng, L. & Nestler, E.J. (2000) J. Neurosci.20, 8965-8971. Nestler, E.J., Barrot, M. & Self, D.W. (2001) Proc. Natl. Acad. Sci. USA98 11042-11046. Figure 3. FosB/∆FosB counts in NAc-shell, NAc-core, and BLA either 2 or 5 weeks following chronic administration of cocaine or saline in animals undergoing novel-object (a) or cocaine (b) place conditioning studies. *p<.01; n = 10-14. Research supported by PHS grants DA06214 and DA017289.