Interrupted expression of NAC-1 augments the behavioral responses to cocaine.
NAC-1 is an mRNA that is increased selectively in the nucleus accumbens after acute and repeated cocaine administration. Antisense or control oligonucleotides were microinjected into the nucleus accumbens of rats to define the role of NAC-1 in the behavioral responses to acute systemic cocaine. Antisense oligonucleotides decreased NAC-1 mRNA levels by 26% and markedly enhanced the motor stimulant response to an acute cocaine injection compared to sense oligonucleotide microinjections. The augmentation in cocaine motor behavior produced by NAC-1 antisense pretreatment in the nucleus accumbens was not associated with increased dopamine release as estimated by microdialysis. In contrast, the behavioral response to dopamine microinjection into the nucleus accumbens was increased after antisense oligonucleotide treatment, while the motor response to mu-opioid receptor stimulation was unaltered. These data suggest that the induction of NAC-1 by cocaine may be a compensatory mechanism that minimizes the behavioral impact of cocaine administration by regulating postsynaptic dopamine transmission within the nucleus accumbens.
Department of Physiology and Neuroscience, Medical University of South Carolina, Charleston, South Carolina 29425, USA. kalivasp@musc.edu
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Kalivas
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Mackler
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004357:Drug Synergism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists; D012097:Repressor Proteins
D004745:Enkephalins; C108190:Nacc1 protein, rat; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; D012097:Repressor Proteins; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D003042:Cocaine; D004298:Dopamine