Dysregulation of System Xc- and Its Impact on Cocaine Seeking

摘要: DYSREGULATION OF SYSTEM XCAND ITS IMPACT ON COCAINE SEEKING Aric Madayag Marquette University, 2012 Abnormal glutamate signaling in the brain, particularly nucleus accumbens core, contributes to compulsive cocaine-seeking behavior. In accumbens, two distinct pools of exist. The synaptic pool stimulates excitatory postsynaptic receptors, leading cocaine seeking. Cystine-glutamate exchange by system xccontributes extrasynaptic and regulates neurotransmission activating receptors including inhibitory Group II metabotropic positioning this as an important mechanism for regulating activity. We others have found decreased levels cystine-glutamate animals withdrawn from chronic administration. chapter 1, we describe studies directly implicating diminished xcactivity abnormal necessary promoting drug Given that altered is essential seeking, understanding cellular basis reduced would advance our knowledge neural addiction. Unfortunately, little known about how regulated. To address this, sought define conditions permit study xc(chapter 2). 3, examined potential regulation xcby dopamine, nonspecific dopamine agonists, D1-liked receptor D2-like agonists. While D1-like mixed cortical culture, did not observe effect tissue punches; thus, it unlikely underlies cocaine-withdrawn animals. 4, pituitary adenylyl cyclase polypeptide (PACAP) because has been recently shown regulate extracellular homeostasis. acute tonic PACAP-induced stimulation Ca 2+ -dependent protein kinase (PKC) More importantly, also determined PACAP xcis self-administration. These findings suggest dysregulated By revealing novel mechanisms contributing addiction, scientists can identify targets therapeutic treatment.