Effect of cocaine on Fas-associated protein with death domain in the rat brain: individual differences in a model of differential vulnerability to drug abuse.
This study was designed to (1) assess the effects of cocaine on Fas-associated protein with death domain (FADD) system and its role in the activation of apoptotic vs nonapoptotic events and (2) ascertain whether animals selectively bred for their differential propensity to drug-seeking show differences in FADD levels or response to cocaine. Acute cocaine, through D(2) dopamine receptors, induced a dose-response increase in FADD protein in the cortex, with opposite effects over pFADD (Ser191/194), and no induction of apoptotic cell death (poly-(ADP-ribose) polymerase cleavage). FADD was increased by cocaine in cytosol (approximately 142%), membranes (approximately 23%) and nucleus (approximately 54%). The modulation of the FADD system showed tolerance of the acute effect over time, as well as a compensatory response on withdrawal that mirrored the acute effect--ie a transient FADD decrease on day 3 of withdrawal, both at mRNA and protein levels. In a second experiment, possible FADD differences were investigated in rats selectively bred for differential responsiveness to novelty, propensity for drug-seeking and cocaine sensitization. High-responders (HR), who were more prone to drug abuse, exhibited higher FADD and lower pFADD levels than low-responder (LR) rats. However, HR and LR rats showed similar rates of cocaine-induced apoptosis, and exhibited a parallel impact of cocaine over FADD within each phenotype. Thus, FADD is a signaling protein modulated by cocaine, regulating apoptosis/proliferative mechanisms in relation to its FADD/pFADD content. Interestingly, animals selectively bred for differential propensity to substance abuse show basal differences in the expression of this protein, suggesting FADD may also be a molecular correlate for the HR/LR phenotype.
García-Fuster
María-Julia
MJ
Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109-0720, USA. juliagf@umich.edu
Clinton
Sarah M
SM
Watson
Stanley J
SJ
Akil
Huda
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016739:Behavior, Addictive / Q000503:physiopathology; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000633:toxicity; D003042:Cocaine / Q000633:toxicity*; D019970:Cocaine-Related Disorders / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism*; D008297:Male; D010641:Phenotype; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D019966:Substance-Related Disorders
D000697:Central Nervous System Stimulants; C505535:Fadd protein, rat; D053200:Fas-Associated Death Domain Protein; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D011065:Poly(ADP-ribose) Polymerases; D003042:Cocaine