title: Increased breakpoints on a progressive ratio schedule reinforced by IV cocaine are associated with reduced locomotor activation and reduced dopamine efflux in nucleus accumbens shell in rats.
abstract: BACKGROUND
  It has been hypothesized that sensitization of the neurochemical effects within the mesolimbic dopamine (DA) system might account for specific aspects of the addiction process. We have recently developed a self-administration procedure which produces increases in responding reinforced by cocaine on a progressive ratio (PR) schedule. This may reflect an increased motivation to self-administer cocaine, one hallmark of addiction.
  
  
  OBJECTIVE
  The goal of this experiment was to investigate behavioral and neurochemical changes associated with increased cocaine self-administration on a PR schedule.
  
  
  METHODS
  Rats self-administered cocaine over 14 days under a PR schedule. Cocaine-stimulated locomotor activity was evaluated before as well as 1 or 14 days after self-administration training. Cocaine-induced DA changes in the core and shell of the nucleus accumbens in the same animals were also examined.
  
  
  RESULTS
  Subjects showed increased responding over time, to about 200% of baseline. Cocaine-induced locomotor activation was decreased at both withdrawal times compared to naïve animals. Microdialysis showed no differences after self-administration in the nucleus accumbens core dopamine response at either time point. There was, however, a significant decrease in the dopamine response to cocaine in the shell of the nucleus accumbens.
  
  
  CONCLUSIONS
  The present results demonstrate that a progressive increase in breakpoints on a PR schedule can be established in rats at a time when the ability of cocaine to increase extracellular DA levels and stimulate locomotor activity is reduced. Therefore, sensitization of the mesolimbic DA system does not account for the observed change in drug-taking behavior.
authors: Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157, USA. clack@wfubmc.edu
authors: Christopher M
authors: CM
authors: Lack
authors: Sara R
authors: SR
authors: Jones
authors: David C S
authors: DC
authors: Roberts
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage* / Q000633:toxicity; D019970:Cocaine-Related Disorders / Q000503:physiopathology*; D004298:Dopamine / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009042:Motivation; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule; D012646:Self Administration; D015819:Substance Abuse, Intravenous / Q000503:physiopathology*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology
chemical_list: D003042:Cocaine; D004298:Dopamine