David N. Kearns

Sign-tracking (autoshaping) in rats: A comparison of cocaine and food as unconditioned stimuli

A series of experiments was performed to determine whether sign-tracking would occur in rats with intravenous (i.v.) cocaine as the unconditioned stimulus. In Experiment 1, a retractable lever paired with food produced strong sign-tracking, but a lever paired with one of three doses of i.v. cocaine did not elicit any approach or contact behavior. Experiment 2 demonstrated that doses of cocaine that did not elicit sign-tracking would function as a positive reinforcer for a lever contact operant. In Experiment 3, an artificialconsummatory response was added to make the cocaine reinforcement episode more behaviorally comparable to that occasioned by food. Although the rats readily performed this response when it was required to receive cocaine infusions, they still did not contact a lever that signaled the availability of these infusions. It appears that cocaine is different from other positive reinforcers (e.g., food, water, warmth, or intracranial stimulation) in that it will not produce sign-tracking in rats.

A comparison of Lewis and Fischer rat strains on autoshaping (sign-tracking), discrimination reversal learning and negative automaintenance

Lewis (LEW) and Fischer (F344) rat strains differ on a number of physiological characteristics, such as hypothalamic-pituitary-adrenal (HPA) axis activity, as well as on behavioral tasks, including those that measure impulsivity and drug reward. Since autoshaping, the phenomenon where animals approach and contact reward-paired conditioned stimuli, has been linked to HPA axis functioning, impulsivity and drug taking, the present study compared LEW and F344 rats on the rate of acquisition and performance of the autoshaping response. Rats were trained on an autoshaping procedure where insertions of one retractable lever (CS(+)) were paired response-independently with food, while insertions of another lever (CS(-)) were not paired with food. LEW rats acquired the autoshaping response more rapidly and also performed the autoshaping response at a higher rate than F344 rats. No differences between the strains were observed when rats were trained on a discrimination reversal where the CS(+) and CS(-) levers were reversed or during a negative auto-maintenance phase where CS(+) lever contacts cancelled food delivery. Potential physiological mechanisms that might mediate the present results, including strain differences in HPA axis and monoamine neurotransmitter activity, are discussed. The finding that LEW (as compared to F344 rats) more readily acquire autoshaping and perform more responses is consistent with research indicating that LEW rats behave more impulsively and more readily self-administer drugs of abuse.

Reinstatement in a cocaine versus food choice situation: reversal of preference between drug and non‐drug rewards

Recent studies show that when given a mutually exclusive choice between cocaine and food, rats almost exclusively choose food. The present experiment investigated potential shifts in preference between levers associated with either food or cocaine that might occur during extinction (food and cocaine no longer available) and during footshock‐induced, cocaine‐primed and food‐primed reinstatement. During self‐administration sessions where food and cocaine were simultaneously available, rats demonstrated a stable food preference, choosing food over cocaine on 83% of trials. During extinction when neither reinforcer was available, no preference between levers was evident and responding decreased until rats responded on the previously food‐ and cocaine‐associated levers at equally low rates. Footshock resulted in a non‐specific reinstatement of responding upon both levers, while cocaine priming resulted in a significant preference for cocaine seeking over food seeking. This suggests that the mechanism underlying footshock‐induced reinstatement is distinct from that of cocaine‐primed reinstatement. Food priming engendered a mild, non‐specific increase in responding on both levers. Although rats generally prefer food over cocaine when presented with a choice between these primary reinforcers, the present results suggest that in certain situations, cocaine‐seeking behavior prevails over food‐seeking behavior.

Conditioned inhibition of cocaine seeking in rats.

Despite its potential relevance to the treatment of drug abuse, conditioned inhibition of drug seeking has not been systematically investigated before. In this study, rats could self-administer cocaine by lever pressing whenever a click or tone was present. Responding was not reinforced when a light was present. The light was presented simultaneously with the click (i.e., in an excitatory context) in 1 group, but the light was always presented alone in another group. When it was later presented in compound with the tone, the light was a highly effective conditioned inhibitor, suppressing cocaine seeking by 92% in the former group and by 74% in the latter. These results suggest ways to improve cue-oriented behavioral treatments for drug abuse.

Conditioned suppression of behavior maintained by cocaine self-administration

Shock-paired stimuli have produced conditioned suppression of behavior maintained by a variety of reinforcers such as food, water, sucrose, and intracranial self-stimulation. With the ongoing pursuit of animal models for drug abuse treatment, it is surprising that this procedure for suppressing positively reinforced behavior has never been applied to drug-maintained behavior. The present study applied the conditioned suppression paradigm to behavior maintained by cocaine self-administration in rats. If shock-paired stimuli suppress ongoing cocaine self-administration, this would contrast with recent studies reporting that aversive stimuli can enhance the acquisition and reinstatement of behavior reinforced by cocaine. Rats were trained to bar-press for intravenous cocaine infusions on a variable-interval schedule. Then, a tone conditioned stimulus (CS) and a light CS were each paired with foot-shock while the rats were bar-pressing for cocaine. These CSs each came to reliably suppress responding in all subjects, just as shock-paired CSs suppressed responding by the positive reinforcers mentioned above. When the tone and the light were presented simultaneously in testing, suppression was significantly enhanced over that controlled by the single CSs. These results demonstrate that (1) cocaine-maintained behavior can be suppressed by environmental stimuli associated with non-drug reinforcers; and (2) combining stimuli that decrease drug self-administration can enhance their suppressive effects. Thus, the present findings can have implications for drug treatment.

A Review of Preclinical Research Demonstrating that Drug and Non-Drug ReinforcersDifferentially Affect Behavior

This review describes and summarizes current preclinical research revealing important differences between drug and non-drug reinforcers in terms of their effects on behavior. Despite research showing that drugs are not especially strong reinforcers in animals, a number of other behavioral differences potentially relevant to addiction have been reported in studies that have compared drug and non-drug reinforcers. Several of these effects appear only after long-term access to drugs. These include an escalation of drug intake, an increased persistence in responding for the drug, and a decreased sensitivity to the effects of punishers or other suppressors of drug seeking. Further differences between drug and non-drug reinforcers include the effects that reinforcer-paired stimuli have on behavior. Drug cues, as compared to food cues, have been shown to exert greater control over reinforcer-seeking behavior after periods of abstinence. Similarly, behavior previously reinforced by drugs, but not food, has been shown to be susceptible to stress-induced reinstatement after extinction. The behavioral differences between drug and non-drug reinforcers reviewed here may identify special features of drugs that lead to addiction.

Strain differences in patterns of drug-intake during prolonged access to cocaine self-administration.

The current study examined possible interactions between genetic factors and prolonged drug access by testing the Fischer (F344), Lewis (LEW), and Wistar rat strains in a prolonged access cocaine self-administration (SA) procedure. Before prolonged access, the strains did not differ in breakpoints for food or cocaine with progressive ratio (PR) testing. The LEW and Wistar rats acquired cocaine SA faster than the F344s. With prolonged access to cocaine SA, the LEW and Wistar rats showed comparable within-session patterns that were higher at the outset of each session and decreased to a stable baseline. Alternatively, the F344 rats began sessions with lower intake and increased their rate of intake during the session. The F344 and Wistar rats took more drug per session than the LEW rats but did not differ from each other. Following prolonged access, the strains did not differ in breakpoints for food, but the Wistar rats had higher breakpoints for cocaine than the F344 rats. Possible underpinnings for the observed strain differences are discussed.

Deepened Extinction of Cocaine Cues

BACKGROUND A method for reducing the power of drug cues could help in treating drug abuse and addiction. Extinction has been used, with mixed success, in such an effort. Research with non-drug cues has shown that simultaneously presenting (compounding) those cues during extinction can enhance the effectiveness of extinction. The present study investigated whether this procedure could be used to similarly deepen the extinction of cocaine cues. METHODS Rats were first trained to self-administer cocaine during tone, click, and light stimuli. Then, these stimuli were subjected to extinction in an initial phase where they were presented individually. In a second extinction phase, one of the auditory stimuli (counterbalanced) was compounded with the light. The other auditory stimulus continued to be presented alone. Rats were then given a week of rest in their homecages prior to testing for spontaneous recovery of cocaine seeking. RESULTS The cue that was compounded with the light during the second phase of extinction training occasioned less spontaneous recovery of cocaine seeking than the cue that was always presented individually during extinction. Increasing the number of compound cue extinction sessions did not produce a greater deepened extinction effect. CONCLUSIONS The present study showed that simultaneously presenting already-extinguished cocaine cues during additional extinction training enhanced extinction. This extends the deepened extinction effect from non-drug cues to drug cues and further confirms predictions of error-correction learning theory. Incorporating deepened extinction into extinction-based drug abuse treatments could help to reduce the power of drug cues.

Drug specificity in drug versus food choice in male rats.

Although different classes of drug differ in their mechanisms of reinforcement and effects on behavior, little research has focused on differences in self-administration behaviors maintained by users of these drugs. Persistent drug choice despite available reinforcement alternatives has been proposed to model behavior relevant to addiction. The present study used a within-subjects procedure, where male rats (Long-Evans, N = 16) were given a choice between cocaine (1.0 mg/kg/infusion) and food (a single 45-mg grain pellet) or between heroin (0.02 mg/kg/infusion) and food in separate phases (drug order counterbalanced). All rats were initially trained to self-administer each drug, and the doses used were based on previous studies showing that small subsets of rats tend to prefer drug over food reinforcement. The goal of the present study was to determine whether rats that prefer cocaine would also prefer heroin. Choice sessions consisted of 2 forced-choice trials with each reinforcer, followed by 14 free-choice trials (all trials separated by 10-min intertrial interval). Replicating previous results, small subsets of rats preferred either cocaine (5 of the 16 rats) or heroin (2 of the 16 rats) to the food alternative. Although 1 of the 16 rats demonstrated a preference for both cocaine and heroin to the food alternative, there was no relationship between degree of cocaine and heroin preference in individual rats. The substance-specific pattern of drug preference observed suggests that at least in this animal model, the tendencies to prefer cocaine or heroin in preference to a nondrug alternative are distinct behavioral phenomena.

Cocaine can generate a stronger conditioned reinforcer than food despite being a weaker primary reinforcer

The present study aimed to test the hypothesis that cues associated with drug‐taking behavior become extra strong motivators of behavior compared with cues paired with non‐drug reinforcers. In experiment 1, rats were trained to lever press for intravenous cocaine infusions and grain pellets. Each reinforcer was paired with a distinct audiovisual cue. When allowed to choose between these alternatives, rats chose grain on ∼70–80 percent of trials. However, after extinguishing lever pressing, reintroduction of press‐contingent cues during a test for cue‐induced reinstatement generated more cocaine seeking than grain seeking (also observed on 3‐ and 8‐week follow‐up tests). To examine whether the same pattern of results would occur with two non‐drug reinforcers, experiment 2 replicated experiment 1 using grain and sucrose as reinforcement alternatives. Rats chose sucrose over grain on ∼70–80 percent of choice trials and also responded more for the sucrose cue than for the grain cue on the reinstatement test. The disconnect between primary and conditioned reinforcements in experiment 1 but not in experiment 2 suggests that drug cues may become exceptionally strong motivators of drug seeking. These results are consistent with cue‐focused theories of addiction and may offer insight into the persistent cue‐driven drug‐seeking behavior observed in addiction.