Cocaine Dose and Self-Administration History, but Not Initial Cocaine Locomotor Responsiveness, Affects Sensitization to the Motivational Effects of Cocaine in Rats

Abstract

Cocaine addiction is a significant and complex disease. Part of this complexity is caused by the variability of the drug experience early in drug use (initial responsiveness, amount of use, etc.). In rats, individual differences in initial cocaine responsiveness and cocaine self-administration history both predict the development of cocaine sensitization, a putative mechanism contributing to the development of cocaine addiction. Here, we sought to determine the role of these factors and cocaine dose on the development of sensitization to cocaine's motivational effects during the earliest stages of self-administration. Rats were classified as either low or high cocaine responders (LCRs or HCRs, respectively) based on acute cocaine-induced locomotor activity (10 mg/kg i.p.) before learning to self-administer cocaine (0.6 mg/kg/infusion i.v.) under a fixed ratio 1 (FR1) schedule of reinforcement. After acquisition, rats self-administered cocaine (0.6 or 1.2 mg/kg/infusion) under a progressive ratio (PR) schedule of reinforcement either immediately or after an additional five FR1 sessions (0.6 or 1.2 mg/kg/infusion). No LCR/HCR differences in sensitization were observed. However, regardless of LCR/HCR classification, exposure to the higher dose of cocaine produced sensitization to cocaine's motivational effects on the PR schedule (i.e., increased break points) and an escalation of consumption on the FR schedule. Thus, our results reveal a novel model for studying escalation and sensitization very early after acquisition and suggest that sensitization may be important in the earliest stages of the cocaine addiction process.

Continuous exposure to dizocilpine facilitates the acquisition and escalation of cocaine consumption in male Sprague-Dawley rats

“…Rats in the first experiment were used to assess the impact of dizocilpine on the acquisition of cocaine self-administration (0.6 mg/kg/infusion; n = 31) and rats in the second experiment were used to assess the impact of dizocilpine on the escalation of cocaine self-administration induced by a switch in cocaine dose (e.g., Mandt et al, 2012b; 0.6 → 1.2 mg/kg group, n = 16; 0.6 → 0.6 mg/kg group, n = 19). All rats were housed individually with ad libitum access to food and water in an animal care facility at the University of Colorado Denver (CU Denver).…”

“…Rats that meet this criterion clearly discriminate the active from inactive levers (Mandt et al, 2012a,b). Further, post-acquisition escalation of consumption of cocaine can be measured in 2 h sessions and is dose-dependent; escalation is observed when rats self-administer 1.2 mg/kg/infusion cocaine but not 0.6 mg/kg/infusion cocaine in daily 2 h self-administration sessions (Mandt et al, 2012b).…”

“…The aim of the present study was to test the effects of continuous infusion of dizocilpine on (1) the acquisition of cocaine selfadministration and (2) the escalation of cocaine self-administration using this novel experimental procedure that allows manipulation at each phase (i.e., acquisition and post-acquisition escalation; Mandt et al, 2012b). Further, dizocilpine was administered via osmotic minipump to minimize the disruptions in behavior that can occur with bolus injections of the drug (e.g., Carter, 1994;Ginski and Witkin, 1994).…”

Effects of Cocaine Sensitization on Drug Self-Administration, Mesocorticolimbic SAPAP Levels, and Prefrontal Ionotropic Glutamate Receptors

“…Sensitization changes on a smaller scale in model organisms are responsible for the maintenance of operant responding for drug [22], and consist of neuronal changes at the molecular [23] and anatomical [24] level. Even though many of the molecular events leading up to, and that occur during sensitization are poorly understood, it is seemingly permanent.…”

“…Rats exposed intermittently to cocaine can be trained to selfadminister drug in conjunction with a cue light activated when cocaine is administered. When extinguished, rats will reinstate their drug-seeking behavior when presented with a cue light, often after long periods of forced abstinence [21].Sensitization changes on a smaller scale in model organisms are responsible for the maintenance of operant responding for drug [22], and consist of neuronal changes at the molecular [23] and anatomical [24] level. Even though many of the molecular events leading up to, and that occur during sensitization are poorly understood, it is seemingly permanent.…”