Rapid extinction of cocaine craving: toward a novel cue exposure

Neuropsychopharmacology, 2001

The conditioning of cocaine's pharmacological actions with environmental stimuli is thought to be a critical factor in long-lasting relapse risk associated with cocaine addiction. To study the significance of environmental stimuli in enduring vulnerability to relapse, the resistance to extinction of drug-seeking behavior elicited by a cocainerelated stimulus was examined. Male Wistar rats were trained to associate discriminative stimuli (S D ) with the availability of intravenous cocaine (S ϩ ) vs. the availability of non-rewarding (S Ϫ ) saline solution, and then placed on extinction conditions during which intravenous solutions and S D were withheld. The rats were then presented with the S ϩ or S Ϫ alone in 60-min reinstatement sessions conducted at 3-day intervals. To examine the long-term persistence of the motivating effects of the cocaine S ϩ , a subgroup of rats was re-tested following an additional three months of abstinence during which time the rats remained confined to their home cages. Re-exposure to the cocaine S ϩ selectively elicited robust responding at the previously active lever. The efficacy and selectivity of this stimulus to elicit responding remained unaltered throughout a 34-day phase of repeated testing as well as following the additional extended abstinence period. In pharmacological tests, conducted in a separate group of rats, the dopamine (DA) D 1 antagonist SCH 39166 (10 g/kg), the D 2/3 antagonist nafadotride (1 mg/kg), and the D 2/3 agonist PD 128907 (0.3 mg/kg) suppressed the cue-induced response reinstatement while the D 1 agonist SKF 81297 (1.0 mg/kg) produced a variable behavioral profile attenuating cue-induced responding in some rats while exacerbating this behavior in others. The results suggest that the motivating effects of cocaine-related stimuli are highly resistant to extinction. The undiminished efficacy of the cocaine S ϩ to induce drug-seeking behavior both with repeated testing and following long-term abstinence parallels the long-lasting nature of conditioned cue reactivity and cue-induced cocaine craving in humans, and confirms a significant role of learning factors in long-lasting vulnerability to relapse associated with cocaine addiction. Finally, the results support a role of DA neurotransmission in cue-induced cocaine-seeking behavior.

Psychopharmacology, 2004

Cocaine seeking over extended withdrawal periods in rats: different time courses of responding induced by cocaine cues versus cocaine priming over the first 6 months Abstract Rationale and objectives: We previously found time dependent increases, or incubation, of cocaine seeking induced by re-exposure to cocaine cues over withdrawal periods of up to 3 months. Here, we studied cocaine seeking induced by re-exposure to cocaine cues or cocaine itself over an extended withdrawal period of 6 months. Methods: Rats were trained to self-administer intravenous cocaine for 6 h/day for 10 days. Cocaine seeking induced by re-exposure to cocaine cues or cocaine itself, as measured in extinction or drug-induced reinstatement tests, respectively, was then assessed 1 day, or 1, 3 or 6 months after withdrawal. Rats were first given six 1-h extinction sessions wherein lever presses resulted in contingent presentations of cues previously paired with cocaine infusions. Subsequently, reinstatement of drug seeking induced by cocaine injections (expt 1: 0, 5, and 15 mg/kg, IP; expt 2: 0, 2.5, and 5 mg/kg) was assessed during three 1-h sessions. Results: Profound time dependent changes in responsiveness to cocaine cues in the extinction tests were observed, with low responding after 1 day, high responding after 1 and 3 months, and intermediate responding after 6 months of withdrawal. In contrast, no significant time dependent changes in cocaine-induced drug seeking were found; acute re-exposure to cocaine effectively reinstated responding at all withdrawal periods. Conclusions: Results indicate that the withdrawal period is a critical modulator of drug seeking provoked by re-exposure to cocaine cues, but not cocaine itself. Results also indicate that while the incubation of responsiveness to cocaine cues is a long lasting phenomenon, it is not permanent.

2007

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 differentialreinforcement-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. operant discriminative appetitive conditioning . Bouton and his associates have investigated the behavioral mechanisms underlying the context renewal effect and have provided persuasive evidence that the effect is not due to the direct excitatory or inhibitory effects of context on responding (

Behavioural Brain Research, 2003

Among cocaine addicts, there is a strong variation in response to relapse provoking factors like conditioned cues and renewed contact with the drug. Here we show that such large individual differences also exist in rats. Reinstatement of extinguished cocaine-seeking behavior was triggered by contingent presentation of a cocaine-conditioned cue or an amphetamine priming injection. We found no positive correlation between cue-and drug-controlled reinstatement of cocaine seeking. Rather, a slight, but significant negative correlation was observed, which was particularly evident in two subgroups of rats that responded highest following either amphetamine priming or cue presentation. A large middle group responded equally for both relapse provoking factors. Further, cocaine-seeking behavior during the first extinction session correlated positively with cue-induced reinstatement. In conclusion, the present findings indicate that the therapeutic efficacy of relapse prevention strategies may depend on individual sensitivity to distinct relapse provoking stimuli.

Behavioural Pharmacology, 2008

Cocaine-associated cues can elicit incentive motivational effects that drive cocaine-seeking behavior and contribute to relapse. The extinction/reinstatement model is commonly used to measure these effects in animals. This study examined the influence of training and testing schedules of reinforcement on cue-elicited reinstatement. Lever presses during training resulted in cues and cocaine (0.75 mg/kg/IV) on either continuous or partial reinforcement schedules [fixed ratio (FR) 1 or 11, variable ratio (VR) 5 or 11]. Animals then underwent extinction training, followed by a test for cue-elicited reinstatement of extinguished cocaine-seeking behavior by responsecontingent cue presentations on either a continuous (FR 1) or a partial reinforcement schedule (FR 11). Partial reinforcement during training resulted in higher response rates during cue-elicited reinstatement relative to continuous reinforcement. In contrast, delivery of cues on a continuous reinforcement schedule during testing yielded higher response rates relative to delivery on a partial reinforcement schedule. Finally, the shift from a partial to a continuous reinforcement schedule across training and testing phases did not alter response rates. These findings provide important information for choosing parameters for reinstatement of drug-seeking behavior that would allow the most sensitive method to detect changes in response rate after an experimental manipulation.

Psychopharmacology, 2006

Rationale: Recent evidence suggests that prolonged cocaine self-administration produces escalation in drug-seeking behavior in rats analogous to the increased intake patterns observed in cocaine-dependent individuals. However, the contributions of prolonged access to cocaine taking vs the pharmacologic effects of the consequent increased cocaine exposure on escalation of drug-seeking behaviors have not been investigated. Objective: The present study assessed the effects of these two factors on maintenance of cocaine self-administration and reinstatement of cocaine seeking. Methods: Male, Sprague-Dawley rats were trained to self-administer cocaine (0.2 mg/i.v. infusion; FR1) for 1 h per day for 10 sessions followed by short access (1 h/day), contingent long access (6 h/day), or noncontingent long access (1 h contingent + 5 h of yoked cocaine infusions/day; i.e., short access + yoked) to cocaine for 14 daily sessions. All rats underwent extinction training and were subsequently tested for the ability of cocaine-paired cues or a cocaine-priming injection (7.5 mg/kg i.p.) to reinstate extinguished cocaine seeking. Results: Rats in all groups maintained stable responding for cocaine reinforcement and subsequently showed significant reinstatement of cocaine-seeking behavior. Conditioned-cued reinstatement was enhanced after the contingent long access and short access + yoked cocaine exposure relative to short access cocaine exposure. Conversely, cocaine-primed reinstatement was enhanced after contingent long-access cocaine exposure relative to the other two conditions. Conclusions: Enhanced drug seeking produced by prolonged daily cocaine self-administration is due to a combination of behavioral and pharmacological factors. Specifically, conditionedcued reinstatement is enhanced by increased cocaine intake and cocaine-primed reinstatement is enhanced by increased cocaine taking.

Physiology & Behavior, 2016

Cocaine addiction is often characterized by a rigid pattern of behavior in which cocaine users continue seeking and taking drug despite negative consequences associated with its use. As such, full acquisition and relapse of drug-seeking behavior may be attributed to a shift away from goaldirected responding and a shift towards the maladaptive formation of rigid and habit-like responses. This rigid nature of habitual responding can be developed with extended training and is typically characterized by insensitivity to changes in outcome value. The present study determined whether cocaine (primary reinforcer) and cocaine associated cues (secondary reinforcer) could be devalued in rats with different histories of cocaine self-administration. Specifically, rats were trained on two schedules of cocaine self-administration (long-access vs. short-access). Following training the cocaine reinforcer was devalued through three separate pairings of lithium chloride with cocaine infusions. Cocaine history did not have an impact on devaluation of cocaineassociated cues. However, the reinforcing properties of cocaine were devalued only in rats on a short-access cocaine schedule but not those trained on a long-access schedule. Taken together this pattern of findings suggests that, in short access rats, devaluation is specific to the primary reinforcer and not associative stimuli such as cues. Importantly, rats that received extended training during self-administration displayed insensitivity to outcome devaluation of the primary reinforcer as well as all associative stimuli, thus displaying rigid behavioral responding similar to behavioral patterns found in addiction. Alternatively, long access cocaine exposure may have altered the devaluation threshold.

Psychopharmacology, 2008

Rationale Cocaine addiction is a relapsing psychiatric disorder with a high prevalence in developed countries. To date, the reinstatement model has been difficult to implement in mice. The design of an appropriate reinstatement model in mice is required in order to use genetically modified animals with the aim of clarifying the mechanisms involved in cocaine relapse. Objectives Our aim was to develop an appropriate model of reinstatement of cocaine-seeking behavior and to investigate the factors that can trigger this reinstatement by using an operant intravenous self-administration procedure in mice. Discrete cues, priming injection of cocaine, and exposure to stress were the stimuli used to reinstate cocaine-seeking behavior. Material and methods Mice were trained to acquire intravenous self-administration of cocaine (1 mg/kg per infusion) on a fixed ratio 1 (FR1) schedule of reinforcement. After achieving the acquisition criteria, animals were led to extinguish the operant behavior. Subsequently, under extinction conditions, mice were tested after the administration of a cocaine priming injection (10 mg/kg i.p.), the presentation of a light cue associated with cocaine administration, or the exposure to a stressful situation (0.21 mA electric footshock). Results Under our experimental conditions the three stimuli successfully reinstated an extinguished cocaine-seeking behavior. Reexposure to cocaine effects by a priming injection was revealed as the strongest stimulus, capable of reinstating cocaine-seeking behavior. Conclusions The effective reinstatement model that we have developed will become a useful tool for future understanding of the neurobiological basis of cocaine addiction and relapse, specifically, with the use of genetically modified mice.

Psychopharmacology, 2003

Rationale: Cocaine abstinence symptoms and conditioned stimuli (CSs) previously associated with cocaine administration are postulated to contribute to relapse to drug taking in humans. Objective: The present study assessed the role of both non-contingent CS presentation and experimenter-imposed extended cocaine-free periods on cocaine-seeking behavior in rats. Methods: A fixed interval (FI) second-order schedule of intravenous cocaine (0.5 mg/infusion) reinforcement of the type FI 15 min (fixed ratio 8:S) was used. Results: Non-contingent CS presentation before exposure to a cocaine binge had no effect on responding under the second-order schedule of reinforcement for cocaine after 23 h of no access to cocaine. By contrast, six noncontingent presentations of the CS during a 1-min period before the test session increased the number of responses in both no-binge (daily 2-h sessions, five infusions) and binge (two 12-h overnight sessions; maximum 48 infusions) exposed rats on day 7 of the cocaine-free period compared to no-binge-and binge-exposed rats that were not presented with the CSs. On day 30 of the cocaine-free period, only binge-exposed rats presented with the CSs exhibited a tendency for increased level of responding. Conclusions: The results indicated that non-contingent CS presentation had no effect after 23 h of no access to cocaine, increased drug-seeking behavior on day 7 of the cocaine-free period independent of binge exposure, and a strong tendency to increase drug-seeking behavior only in binge-exposed rats, on day 30 of the cocaine-free period, illustrating the interactive effects of conditioned stimuli with the extended cocaine-free period.

Journal of Experimental Psychology: Animal Behavior Processes, 2005

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.