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ADDICTION AND REWARD PARAMETERS IN PC2 NULL MICE Kabirullah Lutfy, Ph.D. Desean Lee, M.S. Background • Licit and Illicit Drug abuse has risen • According to Kaiser Family Foundation’s report in 2004 on Prescription drug trends, abuse of prescription drugs has increased due to accessibility • According to a 2010 Nationwide survey by Substance Abuse and Mental Health Services Administration – 540% increase in drug abuse since 1980 – Prevalence of illegal prescription drug abuse has increased 500% since 1990. 2 Opiate addiction and Morphine • Drug addiction is a disease of the brain that results, in part, in the altered endogenous opioid system levels by exogenous agonists. • Morphine is an exogenous opiate agonist that binds to the mu opioid receptor (MOR) and is addictive. • Exogenous opiate agonist, such as morphine, alter levels of endogenous opiates • Chronic morphine up-regulates the mu receptor. Protein Convertase 2 enzyme (PC2) • PC2 mediates the formation of active bendorphin and other endogenous opioids. • PC2 may play an instrumental role in opiate addiction. PC2 Cleaveage sites on POMC Friedman et. al, 2008 5 Hypothesis • We hypothesized that PC2 null mice, by having low levels of exogenous opioids, bendorphin, b-enkephalin and dynorphin, will have an up-regulation of their MOR in brain regions relevant to analgesia, reward and addictive behaviors. MHT Region LH Region WT KO WT *** ***, p< 0.0005 NA Region WT ** WT **, p< 0.005 KO ***, p< 0.0005 PAG Region WT ** **, p< 0.005 KO *** ** WT SSC Region **, p< 0.005 KO VTA Region KO KO *** ***, p< 0.0001 Figure 2: Coronal sections of brain tissues were immunostained against the MOR. We assessed the level of the MOR in brain regions relevant to analgesia, reward and addictive behaviors in PC2 null mice compared to wild type mice using immunohistochemistry. Our results show an up-regulation of the MOR in the Periaqueductal Grey Area (PAG), Ventral Tegmental Area (VTA), Lateral Hypothalamus (LH), Medial Hypothalamus (HT), Nucleus Accumbens (NA), and Somatosensorial Cortex (SSC) regions (P>0.0005), with the highest up-regulation in the PAG and SSC regions. Magnification was set at 64X. Summary • We found that the analgesic, motor stimulatory and rewarding actions of morphine were enhanced in mice lacking PC2 compared to their wild-type littermates/controls. • We also observed that the number of opioid receptors increased in mice lacking PC2 compared to their wild-type controls. • Additionally, we discovered that the number of cell immunostained for the mu opioid receptors were increased in mice lacking PC2 compared to their wild-type mice. These changes were observed in brain regions implicated in nociception, locomotion and reward. Conclusion • The current results suggest that the lack of PC2 enzymes may lead to a decrease in the level of endogenous opioid peptide(s). • The decrease in opioid peptides ’ level leads to enhanced opioid receptors number/density. • The increased receptor number/density is probably responsible for the enhanced pharmacological effects of morphine. • However, further studies are needed to fully characterize the mechanisms underlying the greater sensitivity of mice lacking PC2 to the action of morphine. Acknowledgements • • • • Drupad Parikh (analgesia studies) Paul Marquez (CPP studies) Abdul Hamid (Motor activity studies) Monica Ferrini (immunohistochemistry)