Cocaine cues retain silent traces of an excitatory history after conversion into conditioned inhibitors: 'the ghost in the addict'.

The present experiment investigated the extent to which the A+/AB- conditioned inhibition procedure could counteract an excitatory drug-related conditioning history. In two groups of rats, a light stimulus was established as a signal for the absence of cocaine. For the History group, the light had previously been a discriminative stimulus (S) that occasioned cocaine self-administration and could thus be classified as a cocaine excitor. In comparison, the No-History group first encountered the light during conditioned inhibition training. During conditioned inhibition training, both groups self-administered cocaine during tone as well as during click Ss, whereas drug seeking was eliminated in click-plus-light, wherein cocaine was not available (A+/AB-). Drug seeking was essentially eliminated in both groups. Nevertheless, on a summation test the light reduced cocaine seeking occasioned by the tone S by 95% in the No-History group, but by less than 50% in the History group. This summation test result showed that the effects of a drug-related history persisted even after the light was converted into an effective conditioned inhibitor on the training baseline through the powerful A+/AB- procedure. Future research should seek procedures that produce even stronger conditioned inhibition that eliminates such residual 'silent' drug excitation, the 'ghost in the addict'.

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.

Extinguished cocaine cues increase drug seeking when presented simultaneously with a non-extinguished cocaine cue.

BACKGROUND: Previous research with non-drug reinforcers has shown that simultaneously presenting (compounding) an extinguished cue with another cue formerly associated with the same reinforcer can increase rates of cue-controlled behavior. The present study investigated whether an extinguished cocaine cue would energize cocaine seeking when presented simultaneously with another cocaine cue. This study also investigated whether extinction could be enhanced by subjecting an extinguished cocaine cue to further extinction after administration of reinstating injections of cocaine. METHODS: Rats were first trained to self-administer cocaine in the presence of three different cues. Then, one of the cues was subjected to the standard extinction treatment. Another cue was subjected to a modified extinction treatment where additional extinction sessions were preceded by non-contingent cocaine injections. The third cue was not extinguished. RESULTS: The cue subjected to standard extinction ceased to control cocaine seeking when presented alone, but significantly increased cocaine seeking when compounded with the non-extinguished cocaine cue. The cocaine cue subjected to the modified extinction treatment also significantly increased cocaine seeking occasioned by the non-extinguished cocaine cue. CONCLUSIONS: Extending results of previous studies involving non-drug stimuli, the present study showed that extinguished cocaine cues can enhance cocaine seeking when compounded with other cocaine cues. These results illustrate the persistence of drug cues in controlling behavior despite extinction and highlight the need for developing treatments that eliminate this residual energizing capacity that survives extinction.

Extinction of goal tracking also eliminates the conditioned reinforcing effects of an appetitive conditioned stimulus.

Previous studies have suggested that the effects of extinction are response-specific. The present study investigated whether an extinction treatment that eliminated goal tracking elicited by an appetitive conditioned stimulus (CS) would also eliminate the conditioned reinforcing effects of that CS. Rats were first trained on a goal-tracking procedure in which an auditory CS was paired with a food unconditioned stimulus. Animals learned to approach the location where the food was delivered. In a subsequent phase, rats in one group received extinction training that eliminated the goal-tracking elicited by the CS. Rats in the other group did not experience extinction of the food-paired CS. Then, both groups received a test for conditioned reinforcement in which leverpresses resulted in the brief presentation of the stimulus previously paired with food. This stimulus did not act as a conditioned reinforcer in the group that had been subjected to extinction training, but did serve as a conditioned reinforcer in the group that did not experience extinction. These results indicate that the effects of extinction generalize from the approach-eliciting to the conditioned reinforcing effects of an appetitive CS.

A comparison of explicitly unpaired treatment and extinction: recovery of sign-tracking within a context renewal design.

The present experiment compared the effectiveness of explicitly unpaired treatment and extinction in preventing the recovery of sign-tracking within a context renewal design. Three groups of rats were first trained on a sign-tracking procedure in Context A where insertions of a retractable lever were paired with food. In a second phase, the sign-tracking response was eliminated. One group received standard extinction of the CS in Context B, while another group received explicitly unpaired treatment in Context B where food was presented only during inter-trial intervals (and not paired with the lever). A third group received this explicitly unpaired treatment in Context A. After the sign-tracking response was eliminated, all groups received a test session in Context A where the lever was presented alone and no food was delivered at any time. Significantly more responding occurred in the group that received explicitly unpaired treatment in Context B than in either of the other groups. This demonstrates that there are situations where explicitly unpaired treatment is less effective than extinction in preventing the reappearance of previously eliminated responding.

Learning that a cocaine reward is smaller than expected: A test of Redish's computational model of addiction.

The present experiment tested the prediction of Redish's (2004) computational model of addiction that drug reward expectation continues to grow even when the received drug reward is smaller than expected. Initially, rats were trained to press two levers, each associated with a large dose of cocaine. Then, the dose associated with one of the levers was substantially reduced. Thus, when rats first pressed the reduced-dose lever, they expected a large cocaine reward, but received a small one. On subsequent choice tests, preference for the reduced-dose lever was reduced, demonstrating that rats learned to devalue the reduced-dose lever. The finding that rats learned to lower reward expectation when they received a smaller-than-expected cocaine reward is in opposition to the hypothesis that drug reinforcers produce a perpetual and non-correctable positive prediction error that causes the learned value of drug rewards to continually grow. Instead, the present results suggest that standard error-correction learning rules apply even to drug reinforcers.

Within-subject reversibility of discriminative function in the composite-stimulus control of behavior.

According to the composite-stimulus control model (Weiss, 1969, 1972b), an individual discriminative stimulus (S(D)) is composed of that S(D)'s on-state plus the off-states of all other relevant S(D)s. The present experiment investigated the reversibility of composite-stimulus control. Separate groups of rats were trained to lever-press for food whenever a tone or a light S(D) was present. For one group, the nonreinforced S(Delta) condition was tone-and-light absence (T+L). Tone-plus-light (T+L) was S(Delta) in the other group. On a "stimulus compounding" test that recombined composite elements, maximum responding occurred to that composite consisting only of elements occasioning response increase. That was T+L for the group trained with T+L as S(Delta) and T+L for the group trained with T+L as S(Delta). The S(Delta) composite was next reversed over groups in Phase 2. In Phase 2 tests, maximum responding that was comparable in magnitude to that of Phase 1 was again controlled by the composite consisting only of elements most recently occasioning response increase-whether T+L or T+L. The inhibitory conditioning history of both composite-elements currently occasioning responding did not weaken the summative effect. These results confirm and extend Weiss's composite-stimulus control model, and demonstrate that such control is fully reversible. We discuss how translating conditions of the stimulus-compounding paradigm to a composite continuum creates a functional and logical connection to intradimensional control measured through stimulus generalization, reducing the number of different behavioral phenomena requiring unique explanations.

A comparison of the effects of discriminative and Pavlovian inhibitors and excitors on instrumental responding.

In two experiments, the effects of Pavlovian or discriminative conditioned inhibitors on operant responding were investigated in rats. Experiment 1 found that a Pavlovian conditioned inhibitor for food suppressed food-reinforced lever pressing more than a non-differentially trained control stimulus did. Experiment 2 demonstrated that an operant discriminative inhibitor produced greater suppression of lever pressing than a Pavlovian conditioned inhibitor. Experiment 2 also found that compounding an operant discriminative stimulus (SD) for food-reinforced responding with another SD for food-reinforced responding resulted in more additive summation than when an SD was compounded with a Pavlovian conditioned excitor for food. The results of these experiments support two-factor theories that postulate that incentive and response discriminative processes summate algebraically when the processes are inhibitory or excitatory.

DIFFERENTIAL EFFECTS OF A FOOD-BASED CONDITIONED INHIBITOR ON FOOD- OR COCAINE-SEEKING BEHAVIOR.

The present experiment compared the effects of a food-based conditioned inhibitor on food seeking vs. cocaine seeking behavior. In two groups of rats, the A+/AB- Pavlovian conditioned inhibition procedure was used to create a conditioned inhibitor for food. Then, for one group of rats (Food-Food Group), a click stimulus was established as an operant discriminative stimulus (S(D)) for food-reinforced lever pressing. In the other group (Food-Cocaine Group), the click was established as an S(D) for cocaine self-administration. In testing, the putative inhibitor for food was simultaneously presented with the click for the first time in both groups. In the Food-Food Group, the food-based inhibitor suppressed responding occasioned by the click significantly more than did a neutral control stimulus. In contrast, in the Food-Cocaine Group, there was no difference in the amount of suppression produced by the food-based inhibitor and the control stimulus. These results suggest that the effects of food-based Pavlovian conditioned inhibitors are specific for food-motivated behavior and do not easily transfer to cocaine-motivated behavior.

Reduction of cocaine seeking by a food-based inhibitor in rats.

Environmental stimuli can exert a powerful influence over drug seeking and taking. For example, previous experiments found that combining multiple drug-related stimuli tripled drug seeking and doubled drug intake (L. V. Panlilio, S. J. Weiss, & C. W. Schindler, 1996, 2000), whereas a signal for the absence of cocaine (i.e., a drug-related inhibitor) dramatically reduced cocaine seeking in rats by over 90% (D. N. Kearns, S. J. Weiss, C. W. Schindler, & L. V. Panlilio, 2005). In the present experiment, a signal for the absence of food created through the A+/AB- conditioned inhibition paradigm also suppressed responding for cocaine by approximately 90%. Symmetrically, a signal for the absence of cocaine (i.e., a cocaine-based inhibitor) suppressed food seeking to a similar degree. These findings, consistent with the appetitive-aversive interaction theory of motivation, suggest that using inhibitors based on nondrug appetitive reinforcers might be a practical method of reducing drug seeking in human drug abusers and should be seriously considered for clinical test and application.

Recovery of Pavlovian sign-tracking (autoshaping) following the discontinuation of inter-trial interval food in rats.

In pigeons, Pavlovian autoshaped keypecking produced by keylight-food pairings has been eliminated by introducing food during periods between CS presentations (i.e., during the inter-trial intervals). Keypecking eliminated in this manner reappears when the inter-trial USs are discontinued even though the CS is no longer paired with US. The present experiment investigated whether this recovery of responding produced by discontinuing unpaired inter-trial US presentations could be extended to another species, rats, within a Pavlovian sign-tracking paradigm. Rats were initially trained on a procedure where insertion of one retractable lever (CS(+)) was followed, response independently, with food, while insertion of another lever (CS(-)) was not paired with food. Rats quickly came to contact the CS(+) lever at high rates, but contacted the CS(-) lever infrequently. In the next phase, CS(+) was no longer followed by food. Explicitly unpaired food was presented only during the inter-trial intervals when both levers were absent. This treatment essentially eliminated the sign-tracking response. In the final phase, the unpaired inter-trial food presentations were discontinued while both CSs continued to be presented without food. This produced a significant recovery of the sign-tracking elicited by the CS(+) lever, extending the species generality of the Pavlovian resurgence phenomenon that has previously only been reported in pigeons, to rats.

Stimulus control and compounding with ambient odor as a discriminative stimulus on a free-operant baseline.

Previous experiments have demonstrated that the simultaneous presentation of independently established discriminative stimuli can control rates of operant responding substantially higher than the rates occasioned by the individual stimuli. This "additive summation" phenomenon has been shown with a variety of different reinforcers (e.g., food, water, shock avoidance, cocaine, and heroin). Discriminative stimuli previously used in such studies have been limited to the visual and auditory sensory modalities. The present experiment sought to (1) establish stimulus control on a free-operant baseline with an ambient olfactory discriminative stimulus, (2) compare olfactory control to that produced with an auditory discriminative stimulus, and (3) determine whether compounding independently established olfactory and auditory discriminative stimuli produces additive summation. Rats lever pressed for food on a variable-interval schedule in the presence of either a tone or an odor, with comparable control developed to each stimulus. In the absence of these stimuli responding was not reinforced. During stimulus compounding tests, the tone-plus-odor compound occasioned more than double the responses occasioned by either the tone or odor presented individually. Thus, the current study (1) established stimulus control with an ambient olfactory discriminative stimulus in a traditional free-operant setting and (2) extended the generality of stimulus-compounding effects by demonstrating additive summation when olfactory and auditory discriminative stimuli were presented simultaneously.

Contextual renewal of cocaine seeking in rats and its attenuation by the conditioned effects of an alternative reinforcer.

The present experiment investigated contextual renewal of cocaine seeking and potential methods of attenuating this renewal. Rats were first trained in one context to self-administer cocaine when a discriminative stimulus (tone) was presented. Then, the ABA Group was placed in a second context and responses in tone no longer produced cocaine (extinction). The AAA Group received this extinction in the original context. For two additional groups, responding to the tone was eliminated in a second context by additionally presenting food in tone according to a differential-reinforcement-of-other-behavior (DRO Group) schedule or independently of the rats' behavior on a fixed-time (FT Group) schedule. Renewal of responding to the tone was observed when the ABA Group was returned to the original context for a renewal test, but no renewal was observed in the AAA Group. Renewal also occurred in the DRO and FT Groups upon returning to the original context, but this renewal was significantly less than that of the ABA Group. These results suggest that response elimination techniques that are more active than simple extinction, such as pairing drug-related stimuli with alternative reinforcement, could reduce renewal of drug seeking and thereby help prevent relapse.

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

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 of a food-maintained operant produced by compounding discriminative stimuli.

After a tone and a light were established as discriminative stimuli for food-reinforced responding in rats, presenting these stimuli simultaneously produced over three times as many responses as either the tone or light alone. Following this stimulus compounding test, responses during the tone and during the light were not reinforced (extinction) for 20 sessions, essentially eliminating responding. On stimulus compounding tests administered after the 10th and 20th extinction sessions, tone-plus-light continued to produce significantly more responding than the tone or light alone. The compound even produced responses when the individual stimuli no longer did. These results suggest that the simultaneous presentation of multiple extinguished discriminative stimuli may also contribute to the reinstatement of other positively-reinforced behaviors, such as drug taking.

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.

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 artificial consummatory 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.

Stimulus control of cocaine self-administration.

Environmental stimuli that set the occasion wherein drugs are acquired can "trigger" drug-related behavior. Investigating the stimulus control of drug self-administration in laboratory animals should help us better understand this aspect of human drug abuse. Stimulus control of cocaine self-administration was generated here for the first time using multiple and chained schedules with short, frequently-alternating components--like those typically used to study food-maintained responding. The procedures and results are presented along with case histories to illustrate the strategies used to produce this stimulus control. All these multicomponent schedules contained variable-interval (VI) components as well as differential-reinforcement-of-other-behavior (DRO) or extinction components. Schedule parameters and unit dose were adjusted for each rat to produce stable, moderate rates in VI components, with minimal postreinforcement (infusion) pausing, and response cessation in extinction and DRO components. Whole-body drug levels on terminal baselines calculated retrospectively revealed that all rats maintained fairly stable drug levels (mean, 2.3 to 3.4 mg/kg) and molar rates of intake (approximately 6.0 mg/kg/hr). Within this range, no relation between local VI response rates and drug level was found. The stimulus control revealed in cumulative records was indistinguishable from that achieved with food under these schedules, suggesting that common mechanisms may underlie the control of cocaine- and food-maintained behavior.

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.