Operant drug self-administration and conditioned place preference (CPP) procedures are expansively used in research to model various components of drug reinforcement, consumption, and addiction in humans. In this report, we combined traditional CPP and self-administration methods as a novel approach to studying drug reinforcement and addiction in rats.
Animal models of reinforcement have proven to be useful for understanding the neurobiological mechanisms underlying drug addiction. Operant drug self-administration and conditioned place preference (CPP) procedures are expansively used in animal research to model various components of drug reinforcement, consumption, and addiction in humans. For this study, we used a novel approach to studying drug reinforcement in rats by combining traditional CPP and self-administration methodologies. We assembled an apparatus using two Med Associate operant chambers, sensory stimuli, and a Plexiglas-constructed neutral zone. These modifications allowed our experiments to encompass motivational aspects of drug intake through self-administration and drug-free assessment of drug/cue conditioning strength with the CPP test. In our experiments, rats self-administered cocaine (0.75 mg/kg/inj, i.v.) during either four (e.g., the “short-term”) or eight (e.g., the “long-term”) alternating-day sessions in an operant environment containing distinctive sensory cues (e.g., olfactory and visual). On the alternate days, in the other (differently-cued) operant environment, saline was available for self-infusion (0.1 ml, i.v.). Twenty-four hours after the last self-administration/cue-pairing session, a CPP test was conducted. Consistent with typical CPP findings, there was a significant preference for the chamber associated with cocaine self-administration. In addition, in animals undergoing the long-term experiment, a significant positive correlation between CPP magnitude and the number of cocaine-reinforced lever responses. In conclusion, this apparatus and approach is time and cost effective, can be used to examine a wide array of topics pertaining to drug abuse, and provides more flexibility in experimental design than CPP or self-administration methods alone.
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CPP scores can also be expressed as CPP Difference Scores Percentage (%). In the present study, CPP Difference Score % was calculated first by determining the percent of time spent in each operant chamber using the formula: (Time in Drug (OR Saline) Chamber/Total Time in Each Chamber) * 100 = % Conditioned Place Preference (CPP). The difference score percentage was determined by the formula: (Drug-paired %) – (Saline-paired %) = CPP Difference Score %.
Figure 1. Relationship between Cocaine Intake and Conditioned Place Preference. Pearson’s Correlation analyses determined a significant positive correlation between Total Cocaine-Reinforced Lever Responses and CPP Difference Score % for animals that had self-administered cocaine for eight sessions (e.g., the Long-term group; p < 0.05), but not for animals in the Short-term group (e.g., 4 cocaine sessions). Open diamonds represent individual data points for the Cocaine Long-term (n=9) and filled circles represent the Cocaine Short-term (n= 8) groups. Best-fit lines are dashed for Long-term, and solid for Short-term data points.
Operant intravenous drug self-administration and place conditioning procedures are reliable and valid models for studying the neurobiological bases for drug dependence and addiction 1 2 3. Both methods are widely used in pre-clinical drug abuse research and are able to measure the reinforcing properties of abused drugs 4. However, both methods have shortcomings that the new apparatus and method presented here improves upon 5.
One large drawback of traditional CPP procedures is the non-contingent mode of drug administration. This mode of drug intake has different behavioral and neurochemical outcomes than self-administration 6 7 8 9 10 11 , and is not consistent with human drug-taking experiences. Additionally, unlike drug self-administration procedures, CPP paradigms are unable to measure progressive changes in drug motivation as reflected by increased drug intake; a putative turning point in the switch from recreational drug use to uncontrollable drug addiction. However, drug self-administration behavior has interpretive limitations as well. For instance, response rates are often used to infer reward value, but can be directly influenced by motoric effects of the self-administered drug, independent of the drug’s motivational effects. In addition, the number of drug-reinforced responses can also be influenced by presence or absence of drug infusion-associated stimuli 12.
Cocaine is known to be readily self-administered by rats and produce robust conditioned place preferences at a variety of doses and routes of administration 2 13 14. The results from the present study support previous reports of drug reinforcement models. In addition, a significant positive relationship between cocaine-reinforced lever responses and CPP scores was determined in the Long-, but not the Short-term Cocaine group. These results suggest that place conditioning and self-administration are not necessarily isomorphic measures of reward. For instance, it is conceivable that CPP after short-term cocaine exposure reflects acute reinforcing properties typically seen with initial recreational drug use. On the other hand, in rats with more cocaine experience, cocaine intake escalation in correspondence with increasing levels of conditioned reinforcement may indicate progressive changes in drug sensitivity or enhanced rewarding drug effects in certain populations.
This featured method has utility beyond assessing the positive reinforcing effects of drugs. For instance, aversive effects of drugs not present during initial drug use can emerge with extended drug exposure (e.g., conditioned place aversions, or CPA) and would be detectable using this technique. Additional uses include the potential to screen for subpopulations most sensitive to cocaine-cue associative learning, to assess experience-mediated changes in cocaine-motivated behaviors, and to detect enduring drug-conditioned effects during drug abstinence and/or cued reinstatement. In conclusion, this apparatus and approach is time and cost effective, can be used to examine a wide array of topics pertaining to drug abuse, and provides more flexibility in experimental design than CPP or self-administration methods alone.
The authors have nothing to disclose.
We would like to thank Leah McAleer for her support in conducting this experiment and her help in the poster presentation at the 2009 Society for Neuroscience Meeting and this video production, along with Mohamed Abdalla and Allison Ahrens. We also appreciate Rosie Maddox, Rachel Chavana, and Linda Ju for their assistance in data collection and analyses for this experiment. This project was supported by NIH/NIDA Grant 3R01DA014640-05S1 (C.L.D), The Waggoner Center for Alcohol and Addiction Research Jones Fellowship and NIH/NIAA Training Grant AA07471 (A.A.F). Cocaine HCl was generously supplied by the NIDA Drug Inventory and Supply and Control Program.
Material Name | Tipo | Company | Catalogue Number | Comment |
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Operant Conditioning Behavior (Drug Self-administration) Test Package for Rat | Med Associates, Inc | MED-008-CT-B1 | ||
Infrared Source and Detector (Photobeams) | Med Associates, Inc | ENV-253SD ENV-253 |
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Med PC Software | Med Associates, Inc | SOF-735 | ||
Single speed syringe pump | Razel Scientific Instruments | Model R-E | ||
45 mg sucrose pellets | Bio-Serv | F0042 | ||
Catheter cannula | Plastics One | C313G-5UP | ||
Cocaine | RTI International |