Cocaine-paired Stimuli Research Articles

Differential involvement of dopamine receptors in conditioned suppression induced by cocaine.

Cocaine-paired stimuli can suppress food-reinforced operant behavior in rats, providing an animal model of conditioned drug effects. To study the neuropharmacological basis of this phenomenon, we examined the effects of various dopamine receptor antagonists on the acquisition and expression of cocaine-induced conditioned suppression in rats. Superimposed on an ongoing baseline of food-reinforced operant responding, a stimulus was paired with response-independent cocaine (3.0 mg/kg, i.v.) during each of 8 training sessions. To study acquisition, independent groups of rats were given saline, the dopamine D(1)-like receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390) (0.001-0.03 mg/kg, i.p.), or the dopamine D(2)-like receptor antagonist eticlopride (0.001-0.03 mg/kg, i.p.) prior to each training session. To study expression, independent groups of rats were trained first, then given saline, SCH 23390, eticlopride, or N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide (BP 897) (a dopamine D(3) partial receptor agonist; 0.1-1.0 mg/kg, i.p.) before test sessions in which the stimulus was presented without cocaine. Pre-treatment with either SCH 23390 or eticlopride during acquisition reduced the direct suppressant effects of cocaine, but conditioning was blocked only in rats that were treated with SCH 23390 during acquisition training. Expression of conditioning was attenuated only by eticlopride. Thus, dopamine at least partially mediates both the acquisition and expression of cocaine-induced conditioned suppression, with activation of dopamine D(1)- and D(2)-like receptors underlying these respective processes.

Noradrenergic Mechanisms in Cocaine-Induced Reinstatement of Drug Seeking in Squirrel Monkeys

Norepinephrine (NE) uptake and NE receptor mechanisms play important modulating roles in the discriminative stimulus and stimulant effects of cocaine. The present study investigated the role of NE mechanisms in cocaine priming-induced reinstatement of extinguished drug seeking. Squirrel monkeys (Saimiri sciureus) were trained to stability under a second-order fixed interval, fixed ratio schedule of drug self-administration in which operant responding was maintained jointly by i.v. cocaine injections and presentations of a cocaine-paired stimulus. Drug seeking was then extinguished by replacing cocaine with vehicle and eliminating the cocaine-paired stimulus. In test sessions during which the cocaine-paired stimulus was reintroduced but only vehicle was available for self-administration, priming with cocaine, the dopamine transport inhibitor 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909), and the NE transport inhibitors nisoxetine and talsupram induced dose-dependent reinstatement of drug seeking. The maximum effect of the NE transport inhibitors was less than half that of cocaine. Both nisoxetine and talsupram augmented the priming effects of a low but not a high dose of cocaine. The priming effects of nisoxetine were blocked by the alpha1-adrenoceptor antagonist prazosin, the alpha2-adrenoceptor agonist clonidine, and the beta-adrenoceptor antagonist propranolol, but not by the dopamine receptor antagonist flupenthixol. The priming effects of cocaine were antagonized by clonidine and flupenthixol. Neither nisoxetine nor cocaine increased physiological (salivary cortisol) or behavioral (self-directed behaviors) markers of stress. These findings suggest that NE transporter inhibition and alpha2-adrenoceptor mechanisms play a significant role in cocaine-induced reinstatement of drug seeking that is not secondary to activation of brain stress pathways.

Blocking of conditioning to a cocaine-paired stimulus: Testing the hypothesis that cocaine perpetually produces a signal of larger-than-expected reward

According to a recent account of addiction, dopaminergic effects of drugs like cocaine mimic the neuronal signal that occurs when a natural reward has a larger value than expected. Consequently, the drug's expected reward value increases with each administration, leading to an over-selection of drug-seeking behavior. One prediction of this hypothesis is that the blocking effect, a cornerstone of contemporary learning theory, should not occur with drug reinforcers. To test this prediction, two groups of rats were trained to self-administer cocaine with a nose-poking response. For 5 sessions, a tone was paired with each self-administered injection (blocking group), or no stimulus was paired with injection (non-blocking group). Then, in both groups, the tone and a light were both paired with each injection for 5 sessions. In subsequent testing, the light functioned as a conditioned reinforcer for a new response (lever-pressing) in the non-blocking group, but not the blocking group. Thus, contrary to prediction, pre-training with the tone blocked conditioning to the light. Although these results fail to support a potentially powerful explanation of addiction, they are consistent with the fact that most conditioning and learning phenomena that occur with non-drug reinforcers can also be demonstrated with drug reinforcers.

Pharmacological Stimulation of Group II Metabotropic Glutamate Receptors Reduces Cocaine Self-Administration and Cocaine-Induced Reinstatement of Drug Seeking in Squirrel Monkeys

Group II metabotropic glutamate receptors (mGluRs) have been implicated in regulating the psychopharmacologic effects of cocaine and other drugs of abuse. The present study investigated the interactions between the group II mGluR agonist LY379268 [(-)-2-oxa-4-aminobicyclo [3.1.0] hexane-4,6-dicarboxylate] and cocaine in squirrel monkeys whose operant behavior was maintained under a second order schedule of i.v. cocaine self-administration with or without presentations of a cocaine-paired visual stimulus, extinguished and subsequently reinstated by priming injections of cocaine with or without presentations of a cocaine-paired stimulus, and controlled by cocaine trained as a discriminative stimulus. Antagonism studies with the group II mGluR antagonist LY341495 [2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl) propanoic acid] investigated the extent to which the cocaine-modulating effects of LY379268 could be reversed by blocking group II mGluRs. Quantitative observational studies investigated the effects of LY379268 and LY341495 on species-typical behaviors, balance, and muscle resistance. Pretreatment with LY379268 reduced cocaine self-administration and cocaine-induced reinstatement of drug seeking in a dose-dependent, LY341495-reversible manner. Significant effects of LY379268 were observed both in the presence and absence of the cocaine-paired stimulus. LY379268 did not alter the discriminative stimulus effects of cocaine, nor did it markedly affect observed behavior, with the exception of an increase in visual scanning. Emesis frequently was observed after the highest dose of LY379268 (1.0 mg/kg). The results suggest that LY379268, by stimulating group II mGluRs, can attenuate the reinforcing and priming effects of cocaine at doses that do not alter its perceptibility or markedly suppress other behaviors.

Neural substrates of cocaine-cue associations that trigger relapse

Learned associations that occur during the process of repeated drug use in addiction can later manifest as trigger factors in relapse to renewed drug-seeking and drug-taking behavior. The process of conditioned-cued relapse of drug-seeking behavior has been successfully modeled in animals using the reinstatement procedure, in which chronic drug self-administration can be extinguished or withheld, and then reinstated using conditioned stimuli previously paired with the drug. Our laboratory has extensively studied the neural circuitry underlying conditioned-cued drug-seeking during the expression of reinstatement. In order to study the learning process of drug-cue pairings, we further developed a procedure whereby discrete cocaine-cue pairings can be conducted in a single pavlovian training session in animals previously trained to self-administer cocaine. Presentation of these cues during later reinstatement trials produces robust responding over extinction levels at levels similar to those seen when animals experience the cues on a daily basis. In a series of experiments, we have shown that reversible pharmacological inactivation of the basolateral complex of the amygdala just prior to acquisition of cocaine-cue associations blocks the ability of cocaine-paired stimuli to elicit conditioned-cued reinstatement. This learning process is mediated in part by muscarinic acetylcholine and dopaminergic inputs to the basolateral complex of the amygdala, as intra-amygdala infusion of selective receptor antagonists at the time of acquisition significantly affects reinstatement. We have also recently found that disruption of neural activity within the basolateral complex of the amygdala at the time of consolidation (just after cocaine-cue pairings) will disrupt reinstatement. Taken together, these results reveal the importance of the amygdala in the acquisition, consolidation, and expression of drug-stimulus learning that drives relapse to drug-seeking behavior.

Involvement of the Dorsal Striatum in Cue-Controlled Cocaine Seeking

Through association with the interoceptive effects of drugs of abuse, neutral environmental stimuli can gain motivational properties themselves, becoming conditioned reinforcers that can evoke craving and relapse to drug seeking. Nucleus accumbens dopamine (DA) neurotransmission plays an important role in the reinforcing effect of cocaine itself, but, unlike nucleus accumbens glutamate, it seems not to mediate the conditioned reinforcing properties of cocaine-paired stimuli. Dorsal striatal DA transmission, in contrast, has been shown to be enhanced during cocaine seeking under a second-order schedule of reinforcement, which depends on the conditioned reinforcing properties of cocaine-associated stimuli. Therefore, the aim of the present study was to evaluate the role of DA and glutamate transmission in the dorsal striatum in cue-controlled cocaine seeking. Infusion of the DA receptor antagonist alpha-flupenthixol into the dorsal striatum decreased cocaine seeking under a second-order schedule of reinforcement. In addition, intradorsal striatal infusion of the AMPA/kainate (KA) receptor antagonist LY293558 (3SR, 4aRS, 6RS, 8aRS-6-[2-(iH-tetrazol-5-yl)ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydroiso-quinoline-3-carboxylic acid), but not the NMDA receptor antagonist AP-5, also decreased cue-controlled cocaine seeking. These data show that stimulation of DA and AMPA/KA receptors in the dorsal striatum is critical for well established drug seeking that depends on the reinforcing effects of cocaine-associated stimuli. In addition, given the importance of the dorsal striatum in stimulus-response habit learning, these data suggest that the habitual or compulsive quality of persistent drug seeking depends on dorsal striatal mechanisms.

Interaction of noncontingent cocaine and contingent drug-paired stimuli on cocaine reinstatement

Both noncontingent cocaine and the presentation of cocaine-paired external stimuli will reinstate cocaine-appropriate operant responding. However, the interaction of noncontingent cocaine and cocaine-paired stimuli in producing reinstatement has not been extensively examined. In the present study, the ability of noncontingent cocaine alone, the combination of noncontingent cocaine+contingent cocaine-paired lights+tone and contingent lights+tone alone to produce reinstatement were examined. No cocaine dose (3, 10, 17 mg/kg) produced significant reinstatement in the absence of cocaine-paired lights+tone. When responding also resulted in lights+tone presentation, all doses of cocaine produced similar, significant reinstatement. Finally, when only response contingent lights+tone were presented, none of the groups showed significant reinstatement. These findings indicate that in isolation, noncontingent cocaine alone and cocaine-paired external stimuli may be insufficient to engender significant levels of reinstatement, but when presented together produce robust reinstatement. The results highlight the important interaction between drug administration and drug-paired environmental stimuli in the reinstatement model.

Conditioned stimulus-induced reinstatement of extinguished cocaine seeking in C57BL/6 mice: a mouse model of drug relapse

The scarcity of mouse models for relapse to cocaine seeking has curtailed the study of genetic factors that may contribute to susceptibility for drug relapse. To contribute to the development of a new mouse model of drug relapse, C57BL/6 (B6) mice were trained to press a lever for infusions of cocaine (0.35 mg/kg, i.v.) on a fixed ratio 1 schedule of reinforcement during daily 2-h sessions. A light+tone stimulus complex was presented simultaneously with each cocaine infusion. Mice then underwent a series of extinction sessions during which lever presses had no scheduled consequences. As a result, lever pressing gradually declined. In experiment 1, the ability of the cocaine-paired light+tone stimulus complex to reinstate extinguished cocaine-seeking behavior (i.e. non-reinforced responses) was assessed. In experiment 2, the ability of cocaine priming (0, 1, 2.5, 5, 10, 20, and 40 mg/kg, i.p.) to reinstate cocaine-seeking behavior was measured. B6 mice failed to reinstate in response to i.p. cocaine priming; however, they exhibited robust conditioned stimulus-induced reinstatement. These findings suggest that conditioned stimulus-induced reinstatement in B6 mice is a promising model to study genetic and neurobiological factors that alter the ability of cocaine-paired stimuli to elicit relapse to cocaine seeking behavior.

Drug Addiction, Relapse, and the Amygdala

Evidence has extensively implicated the amygdala in the associative learning process for appetitive reinforcers. Recent interest has focused on the role of the amygdala in the learned associations that occur during the process of drug addiction and relapse. Using an animal model of relapse after chronic cocaine self-administration, we found that rats reinstate extinguished lever responding for conditioned stimuli (tone + light) previously paired with cocaine or heroin ("conditioned-cued reinstatement"). The basolateral amygdala (BLA) complex plays a critical role in this behavior, because permanent lesions or reversible pharmacologic inactivation of the BLA attenuates conditioned-cued reinstatement without affecting cocaine self-administration or cocaine-primed reinstatement. Conditioned-cued reinstatement appears to be mediated in part by dopamine inputs to the BLA, as intra-BLA infusion of a dopamine D1 receptor antagonist blocks reinstatement, whereas intra-BLA infusion of amphetamine potentiates reinstatement. Furthermore, the BLA is also necessary for acquisition of associative learning with cocaine-paired stimuli. Disruption of neural activity within the BLA by sodium channel blockade or muscarinic receptor blockade just before acquisition of stimulus-cocaine associations blocks the ability of conditioned stimuli to elicit conditioned-cued reinstatement after extinction. Together, these results reveal the importance of the amygdala as part of a corticolimbic circuit mediating both the acquisition and the expression of conditioning that plays a critical role in relapse to drug-seeking behavior.

Attenuation of relapse to cocaine seeking by dopamine D1 receptor agonists and antagonists in non-human primates

Dopamine D(1) receptor agonists and antagonists attenuate reinstatement of cocaine seeking in a non-human primate model of relapse. The mechanisms by which these different classes of D(1) receptor drugs produce these similar effects on cocaine seeking are unknown. This study investigated how D(1) receptor agonists and antagonists alter the shape and position of the dose-response function for reinstatement of drug seeking induced by a cocaine prime accompanied by restoration of the cocaine-paired stimulus. Squirrel monkeys were given extensive histories of cocaine self-administration under a second-order fixed-interval, fixed-ratio schedule of i.v. drug injection. Drug seeking was then extinguished by replacing cocaine with vehicle and eliminating the cocaine-paired stimulus. In subsequent test sessions, in which the cocaine-paired stimulus was re-introduced, priming injections of cocaine alone or combined with the different D(1) receptor high- and low-efficacy agonists and antagonists (SKF 82958, SKF 81297, SKF 83959, ecopipam; n=3-4 per drug condition) were tested for their ability to reinstate extinguished cocaine seeking. Cocaine priming accompanied by the restoration of the cocaine-paired stimulus induced a dose-dependent reinstatement of drug seeking. When combined with cocaine, all D(1) receptor agonists and antagonists produced rightward and downward shifts in the cocaine dose-response function. However, combined pretreatment of SKF81297 (agonist) and ecopipam (antagonist) inhibited cocaine seeking less than either drug individually. These findings suggest that D(1) receptor high- and low-efficacy agonists as well as antagonists attenuate reinstatement of cocaine seeking in part via pharmacologically opposing actions at a common population of D(1) receptors.

D1-receptor drugs and cocaine-seeking behavior: investigation of receptor mediation and behavioral disruption in rats.

Dopamine D1-receptor antagonists and agonists both attenuate cocaine-seeking behavior (i.e., operant responding in the absence of cocaine reinforcement) elicited by a cocaine prime or cocaine-paired stimuli. It remains unclear whether these effects are D1-receptor mediated. The present study tested whether a D1 antagonist (SCH-23390) would reverse the attenuating effects of a D1 agonist (SKF-81297) on cocaine-seeking behavior and whether behavioral disruption is involved in these effects. Rats trained to press a lever for cocaine reinforcement with light and tone cues paired with each infusion underwent daily extinction sessions during which responding had no scheduled consequences (i.e., neither cocaine nor the cocaine-paired stimulus complex was available). After responding diminished, the effects of the D1 antagonist on the dose-response functions of the D1 agonist for reinstatement of cocaine-seeking behavior by response-contingent cue presentations or cocaine priming were examined. A separate experiment assessed the effects of the agonist on the dose-response function of the antagonist for cue reinstatement. Stereotyped behavior and activity were also measured during each test session. The attenuating effects of SKF-81297 on cocaine-seeking behavior during cocaine-primed reinstatement were reversed by co-administration of SCH-23390. However, no evidence for reversal of the attenuation during cue reinstatement was found even though agonist-induced stereotypy and antagonist-induced hypoactivity were reversed by co-administration of the two drugs during the same test session. The findings suggest that the attenuating effects of D1-receptor drugs on cocaine-seeking behavior during cocaine reinstatement are mediated by dopamine D1 receptors; however, it remains unclear whether the effects of these drugs on cocaine-seeking behavior during cue reinstatement are D1-receptor mediated. Nevertheless, it is evident that the attenuation of cocaine-seeking behavior by these drugs is not simply due to behavioral disruption.

Selective inactivation of the dorsomedial prefrontal cortex and the basolateral amygdala attenuates conditioned-cued reinstatement of extinguished cocaine-seeking behavior in rats.

Environmental stimuli previously paired with cocaine can induce craving in humans and reinstate extinguished cocaine-seeking behavior in laboratory animals. Previous evidence has implicated the amygdala and the prefrontal cortex (PFC) as possible substrates for conditioned-cued relapse. In order to test directly the role of the PFC in a model of relapse, the present study examined the effects of reversible inactivation of three medial PFC areas, the anterior cingulate (ACing), the prelimbic cortex (PL), and the infralimbic cortex (IL), on the expression of conditioned-cued reinstatement of extinguished cocaine-seeking behavior. We also tested the involvement of the basolateral amygdala (BLA) and the parietal cortex immediately dorsal to the BLA, sensory cortex area 1 - barrel field (S1BF). During daily 3-h sessions, rats pressed a lever for IV cocaine infusions that were paired with a light-tone (LT) presentation. Following extinction of lever pressing in the absence of the LT, reinstatement of extinguished lever pressing was measured during response-contingent presentations of the LT in the absence of cocaine. For localized reversible inactivation, tetrodotoxin (TTX) (5 ng/0.5 micro l/side) or vehicle was bilaterally infused just prior to reinstatement testing. TTX inactivation of the BLA, ACing, or PL impaired the ability of LT presentations to reinstate extinguished lever pressing for cocaine-paired stimuli. In contrast, inactivation of the IL or the S1BF had no effect on conditioned-cued reinstatement. Furthermore, there was no effect of TTX in any of the tested brain regions on general locomotor activity. CONCLUSIONS. These results support a role for the dorsomedial PFC and the BLA in the circuitry that mediates drug-seeking behavior elicited by cocaine-associated stimuli. Placed within the context of recent studies using drug-primed and stress-induced reinstatement models, we suggest that the dorsomedial PFC may serve as a common link in the neural circuitry underlying reinstatement of drug-seeking behavior.

Effects of excitotoxic lesions of the basolateral amygdala on cocaine-seeking behavior and cocaine conditioned place preference in rats

Incentive motivation for cocaine, elicited by cocaine-associated stimuli, is thought to be involved in craving and relapse. To examine the role of the basolateral amygdala complex (BLC) in this phenomenon, we assessed the effects of post-training BLC lesions on extinction of cocaine-seeking behavior and cocaine-conditioned place preference (CPP) and the effects of pre-training BLC lesions on acquisition of cocaine-CPP. In Experiment 1, rats were first trained to self-administer cocaine and then received bilateral infusions of the excitotoxin, N-methyl- d-aspartic acid (NMDA, 0.12 M; 0.3 μl/side), or vehicle into the BLC. They were then tested repeatedly for extinction of cocaine-seeking behavior (i.e. nonreinforced responses in the presence of cocaine-paired stimuli). Subsequently, they were trained and tested for acquisition of cocaine-CPP (i.e. increased time spent in a previously cocaine-paired, relative to a saline-paired, environment). Locomotion and compartment entries were also measured. In Experiment 2, rats were first trained and tested for cocaine-CPP, and then received NMDA or vehicle infusions into the BLC. Subsequently, they were tested repeatedly for extinction of cocaine-CPP. Post-training BLC lesions retarded extinction of cocaine-seeking behavior and cocaine-CPP, whereas pre-training lesions disrupted acquisition of cocaine-CPP. These effects did not appear to be related to changes in general activity. We suggest that pre-training BLC lesions disrupted acquisition of cocaine-CPP by impairing assignment of incentive value to cocaine-paired stimuli, whereas post-training BLC lesions disrupted extinction of cocaine-conditioned behaviors by impairing the assessment of the current incentive value of cocaine-paired stimuli.

A dopamine D3 receptor partial agonist blocks the expression of conditioned activity.

The partial dopamine D3 receptor agonist BP 897 attenuates cocaine seeking suggesting that BP 897 will attenuate conditioned activity to environmental stimuli paired with amphetamine. During conditioning, amphetamine (2.0 mg/kg) stimulated activity and co-treatment with BP 897 (1.0 mg/kg) had no effect. In the saline test, groups conditioned with amphetamine or amphetamine plus BP 897 showed conditioned activity. Treatment with BP 897 in the test following conditioning with saline produced no significant effect but following conditioning with amphetamine BP 897 blocked conditioned activity. Results extend previous findings that BP 897 attenuates responding for cocaine-paired stimuli to amphetamine-paired stimuli in a different paradigm and support the potential of BP 897 as a therapeutic agent for the prevention of drug seeking.

Blockade or stimulation of D1 dopamine receptors attenuates cue reinstatement of extinguished cocaine-seeking behavior in rats.

D(1) dopamine receptor antagonists and agonists attenuate cocaine reinstatement of cocaine-seeking behavior (i.e., responding in the absence of cocaine reinforcement). The present study investigated the effects of a D(1) antagonist (SCH-23390), partial agonist (SKF-38393), and full agonist (SKF-81297) on reinstatement of cocaine-seeking behavior elicited by presentation of cocaine-paired cues. Rats that had been trained to self-administer cocaine with a light/tone stimulus complex paired with each infusion underwent extinction across days. After responding diminished, rats were given response-contingent access to the cocaine-paired stimulus complex. The effects of SCH-23390 (0-10.0 microg/kg), SKF-38393 (0-3.0 mg/kg), and SKF-81297 (0-3.0 mg/kg) on cue reinstatement of cocaine-seeking behavior were examined. The ability of the two D(1) agonists to independently reinstate cocaine-seeking behavior and the effects of SKF-81297 on cocaine reinstatement were also examined. To investigate the possibility of behavioral interference, the effects of SKF-38393 and SKF-81297 on grooming and stereotypy were assessed. SCH-23390 and SKF-81297, but not SKF-38393, attenuated cue reinstatement. However, while SKF-81297 dose-dependently increased response latency, SCH-23390 did not. SKF-81297 also independently reinstated responding at the two lowest doses tested while SKF-38393 had no effect. Furthermore, SKF-81297 decreased cocaine reinstatement and increased response latency only at the highest dose. Finally, stereotypy was observed at all doses of SKF-81297 that also decreased responding, although the patterns of changes in these behaviors did not completely correspond. While the antagonist and full agonist produced similar effects on cocaine-seeking behavior, only the agonist increased response latency, suggesting that different processes mediate the effects of these drugs.

Serotonin depletion attenuates cocaine seeking but enhances sucrose seeking and the effects of cocaine priming on reinstatement of cocaine seeking in rats.

Acute serotonin (5-HT) depletion by the tryptophan hydroxylase inhibitor, para-chlorophenylalanine, attenuates cocaine seeking in rats. The present study examined the effects of chronic 5-HT depletion on cocaine- and sucrose seeking using the 5-HT-selective neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). Separate groups of rats were trained to lever press for cocaine infusions (0.33 mg/kg/0.1 ml, i.v.) or for sucrose pellets (45 mg Noyes) on a fixed ratio (FR) 1 schedule of reinforcement during daily 2-h sessions. Subsequently, animals received i.c.v. infusions of either vehicle or 5,7-DHT (150 microg/6 microl or 200 microg/20 microl). After a minimum of 10 days post-lesion, cocaine- and sucrose seeking were measured as lever presses in the absence of reinforcement (extinction). Some cocaine-trained animals were also assessed for the re-establishment of self-administration and reinstatement of extinguished cocaine seeking by i.v. cocaine priming injections and response-contingent presentations of cocaine-paired stimuli. 5-HT depletion by the 150 microg/6 microl dose of 5,7-DHT failed to alter cocaine- and sucrose seeking despite producing a 42-77% depletion of 5-HT in limbic terminal regions. The 200 microg/20 microl dose of 5,7-DHT attenuated cocaine seeking but enhanced sucrose seeking during extinction and produced a 55-85% depletion of 5-HT. In addition, cocaine-paired cues and cocaine priming reinstated cocaine-seeking behavior, and responding was enhanced in 5,7-DHT-treated animals relative to vehicle-treated controls at the 1 mg/kg/0.1 ml priming dose. However, re-establishment of cocaine self-administration was not altered by 5,7-DHT. The results suggest that 5-HT depletion may attenuate cocaine seeking but may enhance sucrose seeking when animals are tested during extinction. Furthermore, 5-HT depletion may enhance cocaine seeking produced by cocaine itself. Together these findings suggest that 5-HT depletion may have opposite effects on incentive motivation for cocaine during abstinence versus relapse.

Passive exposure to a contextual discriminative stimulus reinstates cocaine-seeking behavior in rats

A significant problem in treating cocaine dependence is craving-induced relapse elicited by inadvertent (i.e., passive) exposure to cocaine-paired stimuli. Extinction/reinstatement of cocaine-seeking behavior in animals has been used to investigate this phenomenon. Most studies using this model have examined reinstatement by response-contingent exposure to discrete cocaine-paired stimuli. The present study expanded this research by examining passive (i.e., not contingent upon an operant response) exposure to a contextual cocaine-paired stimulus to better model craving elicited by inadvertent exposure to cocaine-associated environmental stimuli. Rats underwent daily cocaine and saline self-administration sessions that were identical to each other except for a discriminative stimulus (scented bedding) signaling cocaine availability (S+) or nonavailability (S−). Subsequently, they were placed into the self-administration chambers in the presence of neutral bedding. Reinforcement was not available and cocaine-seeking behavior (i.e., nonreinforced operant responses) was extinguished across days. Rats were then reintroduced to the S+ and S− stimuli. Presentation of the S+, but not the S−, elicited significant reinstatement of cocaine-seeking behavior. The results demonstrate that passive exposure to a contextual discriminative stimulus reinstates extinguished cocaine-seeking behavior. Furthermore, we suggest that reinstatement of cocaine-seeking behavior by passive exposure to cocaine-paired stimuli may provide a model of craving-induced relapse elicited by inadvertent exposure to a cocaine-associated environment.

Stimulus compounding enhances conditioned suppression produced by cocaine-paired stimuli.

Stimulus compounding enhances conditioned suppression produced by cocaine-paired stimuli.

Stimulus compounding enhances conditioned suppression produced by cocaine-paired stimuli.

When 2 stimuli that occasion cocaine self-administration are presented in compound, their ability to increase cocaine-reinforced operant responding is substantially enhanced. The goal of the present experiment was to determine whether stimulus compounding could produce analogous enhancements of a classically conditioned drug effect. Food-maintained responding in rats was suppressed by a tone and a light that were individually paired with response-independent cocaine (3 mg/kg iv). This conditioned suppression was significantly enhanced when the stimuli were presented together in a stimulus-compounding test. The magnitude of this enhancement was similar to that in previous studies in which responding was suppressed by shock-paired stimuli. These results demonstrate that multiple drug-related cues interact in a predictable manner to influence both operant and classically conditioned behavior.

Pharmacological and Environmental Determinants of Relapse to Cocaine-Seeking Behavior

Animal models have been developed that simulate relevant features of relapse to cocaine-seeking behavior in humans. These models have provided valuable information about pharmacological and environmental factors that precipitate reinstatement of extinguished cocaine-seeking in rats and monkeys, as well as new insights about potential pharmacotherapies for relapse prevention. Reinstatement of cocaine-seeking behavior in animals can be induced by cocaine priming or by cocaine-paired environmental stimuli; however, maximum reinstatement of drug-seeking appears to be induced when cocaine priming and cocaine-paired stimuli are combined. Drugs that share cocaine's indirect dopamine agonist properties or that act as direct agonists at D 2-like dopamine receptors also induce reinstatement of cocaine-seeking behavior, whereas with some exceptions (e.g., caffeine, morphine) drugs from other pharmacological classes do not. D 1-like receptor agonists block rather than mimic the priming effects of cocaine, suggesting different roles for D 1- and D 2-like receptor mechanisms in cocaine relapse. Although considerable overlap exists, drugs that exhibit cocaine-like discriminative stimulus and/or reinforcing effects in other situations do not invariably induce cocaine-like reinstatement of drug-seeking and vice versa, implying that these effects are not simply different behavioral expressions of a unitary neurobiological process. Finally, recent findings with D 1-like receptor agonists, partial agonists, and antagonists suggest that some of these drugs may be viable candidates for development as antirelapse pharmacotherapies.