Bruce H. Mandt

Rats classified as low or high cocaine locomotor responders: A unique model involving striatal dopamine transporters that predicts cocaine addiction-like behaviors

Individual differences are a hallmark of drug addiction. Here, we describe a rat model based on differential initial responsiveness to low dose cocaine. Despite similar brain cocaine levels, individual outbred Sprague-Dawley rats exhibit markedly different magnitudes of acute cocaine-induced locomotor activity and, thereby, can be classified as low or high cocaine responders (LCRs or HCRs). LCRs and HCRs differ in drug-induced, but not novelty-associated, hyperactivity. LCRs have higher basal numbers of striatal dopamine transporters (DATs) than HCRs and exhibit marginal cocaine inhibition of in vivo DAT activity and cocaine-induced increases in extracellular DA. Importantly, lower initial cocaine response predicts greater locomotor sensitization, conditioned place preference and greater motivation to self-administer cocaine following low dose acquisition. Further, outbred Long-Evans rats classified as LCRs, versus HCRs, are more sensitive to cocaines discriminative stimulus effects. Overall, results to date with the LCR/HCR model underscore the contribution of striatal DATs to individual differences in initial cocaine responsiveness and the value of assessing the influence of initial drug response on subsequent expression of addiction-like behaviors.

Individual differences in initial low-dose cocaine-induced locomotor activity and locomotor sensitization in adult outbred female Sprague–Dawley rats

Sex and individual differences are important considerations when studying cocaine responsiveness. We have previously shown that male Sprague-Dawley (S-D) rats can be classified as low or high cocaine responders (LCRs or HCRs, respectively) based on their locomotor activity following a single dose of cocaine (10 mg/kg, i.p.). Further, this distinction was found to predict dopamine transporter function, cocaine-induced locomotor sensitization, cocaine conditioned place preference and motivation to self-administer cocaine. Here we investigated whether or not individual differences in cocaine-induced locomotor activity and locomotor sensitization exist in female S-D rats. Female rats exhibited a broad range of locomotor activation following either a 5 or 10 mg/kg cocaine injection, allowing for classification as LCRs or HCRs. When administered over 7 days, both doses induced locomotor sensitization in female LCRs/HCRs. However, the magnitude of effects produced by 5 mg/kg cocaine in female LCRs/HCRs was more comparable to that produced by 10 mg/kg in male LCRs/HCRs, both of which, interestingly, developed sensitization in this study. These findings suggest that female S-D rats, like male S-D rats, can be classified as LCRs/HCRs and highlight the importance of accounting for dose when studying sex and individual differences to the effects of cocaine.

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

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 cocaines 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 cocaines 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.

Escalation of cocaine consumption in short and long access self-administration procedures.

BACKGROUND Escalation of consumption is a hallmark of cocaine addiction. Many animal models reveal escalation by increasing the duration of drug access (e.g., 6-24 h/day) after longer histories of self-administration. We recently developed a method that reveals escalation early post-acquisition under shorter access conditions. However, whether or not rats will escalate cocaine consumption both early post-acquisition under short access (2 h/day) conditions, and later under long access (6 h/day) conditions, has not been demonstrated. METHODS All rats acquired cocaine self-administration (0.8 mg/kg, i.v.) under 2 h conditions, and then continued 2h self-administration for an additional 13 sessions. Then, rats were assigned either to 2 or 6h conditions, and self-administered cocaine (0.8 mg/kg, i.v.) for an additional 19 sessions. In addition, four cocaine-induced locomotor activity measurements were taken for each rat: before cocaine exposure, after non-contingent cocaine administration, and after escalation in the short and long access experimental phases. RESULTS Following acquisition, rats displayed a robust escalation of intake during 2 h sessions. Rats that self-administered cocaine in continued 2h sessions exhibited stable intake, whereas rats that self-administered cocaine in 6h sessions further escalated intake. Despite the second escalation in 6h rats, cocaine-induced locomotor activity did not differ between 2 and 6h rats. CONCLUSIONS Escalation of cocaine self-administration can occur in the same rats both early post-acquisition, and later under long access conditions. Importantly, this early post-acquisition period provides a new opportunity to determine the mechanisms first involved in the escalation phenomenon.