title: Firing rate of nucleus accumbens neurons is dopamine-dependent and reflects the timing of cocaine-seeking behavior in rats on a progressive ratio schedule of reinforcement.
abstract: The progressive ratio (PR) schedule of reinforcement is used to determine the reinforcing properties of rewards such as drugs of abuse. In this schedule, the animal is required to press a lever a progressively increasing number of times to receive a reward; the highest ratio obtained before the animal ceases responding is termed "breakpoint." We recorded neuronal spike activity from cells in the nucleus accumbens (NAc) of rats responding on a PR schedule for cocaine reinforcement. A common subtype of NAc cells demonstrated firing rates that varied according to the time between cocaine deliveries. The firing rate was inversely related to the NAc cocaine level predicted by a pharmacokinetic model. At higher response-to-reward ratios, inter-reward intervals were increased, resulting in a decrease in modeled cocaine level and a concomitant increase in firing rate over the session. The final increase in firing rate above a threshold value suggests a neural correlate of breakpoint. The effects of preadministration of dopamine D1 or D2 antagonists on the animals' behavior were similar in that both reduced breakpoint; however, each antagonist had markedly different effects on NAc cell firing. The D1 antagonist SCH23390 reduced firing rates, even at low cocaine levels, whereas the D2 antagonist eticlopride induced a rightward shift in the dose dependence of NAc cell firing relative to modeled cocaine level. Our results suggest that the firing of NAc cells reflects changes in cocaine levels and thereby contributes to the temporal spacing of self-administration and to the cessation of responding at breakpoint.
authors.affiliation: Center for the Neurobiological Investigation of Drug Abuse, Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. nicola@phy.ucsf.edu
authors.forename: S M
authors.initials: SM
authors.lastname: Nicola
authors.forename: S A
authors.initials: SA
authors.lastname: Deadwyler
mesh_terms: D000818:Animals; D001070:Appetitive Behavior / Q000187:drug effects; D003042:Cocaine / Q000008:administration & dosage; D004298:Dopamine / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists; D004567:Electrodes, Implanted; D007275:Injections, Intravenous; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology*; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors; D012055:Reinforcement Schedule; D012201:Reward; D012646:Self Administration
chemical_list: D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D003042:Cocaine; D004298:Dopamine