Acute, but not longer-term, exposure to environmental enrichment attenuates Pavlovian cue-evoked conditioned approach and Fos expression in the prefrontal cortex in mice.

Exposure to environmental enrichment can modify the impact of motivationally relevant stimuli. For instance, previous studies in rats have found that even a brief, acute (~1 day), but not chronic, exposure to environmentally enriched (EE) housing attenuates instrumental lever pressing for sucrose-associated cues in a conditioned reinforcement setup. Moreover, acute EE reduces corticoaccumbens activity, as measured by decreases in expression of the neuronal activity marker "Fos." Currently, it is not known whether acute EE also reduces sucrose seeking and corticoaccumbens activity elicited by non-contingent or "forced" exposure to sucrose cues, which more closely resembles cue exposure encountered in daily life. We therefore measured the effects of acute/intermittent (1 day or 6 day of EE prior to test day) versus chronic (EE throughout conditioning lasting until test day) EE on the ability of a Pavlovian sucrose cue to elicit sucrose seeking (conditioned approach) and Fos expression in the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), and nucleus accumbens (NAc) in mice. One day, but not 6 day or chronic EE , reduced sucrose seeking and Fos in the deep layers of the dorsal mPFC. By contrast, 1 day, 6 day, and chronic EE all reduced Fos in the shallow layers of the OFC. None of the EE manipulations modulated NAc Fos expression. We reveal how EE reduces behavioral reactivity to sucrose cues by reducing activity in select prefrontal cortical brain areas. Our work further demonstrates the robustness of EE in its ability to modulate various forms of reward-seeking across species.

Examining persistence of acute environmental enrichment-induced anti-sucrose craving effects in rats.

A single, overnight (acute) environmental enrichment (EE; a large environment with conspecifics and novel objects) experience robustly decreases sucrose consumption (taking) and responsiveness to sucrose-paired cues (seeking) in rats. Persisting effects of acute EE on sucrose seeking and taking have not yet been identified. In the present study, rats were trained to self-administer a 10% sucrose solution paired with a compound tone + light stimulus for 10 days in 2-h sessions. We then examined the persistence of acute EE effects at reducing sucrose seeking and taking in a 12-h test immediately following acute EE (Exp. 1), or for 7 days with daily 1-h tests immediately following acute EE, or after a 24-h delay (Exp. 2). We also examined the persistence of acute EE effects on sucrose taking in rats responding on a PR schedule in 7 daily sessions following acute EE (Exp. 3). We found that acute EE was effective at reducing responding for both sucrose and a sucrose-paired cue, persisting throughout the 12-h test (Exp. 1). A reduction in sucrose seeking persisted for 24 h and a reduction in sucrose taking persisted for 72 h following acute EE plus a 24-h delay prior to testing (Exp. 2). Decreased PR responding for sucrose was observed following acute EE; this reduction persisted for 48 h (Exp. 3). These findings indicate that acute exposure to EE has persisting effects at reducing sucrose seeking and taking in rats. Acute EE may have translational value as a non-pharmacological intervention to curb sucrose craving.

Extended exposure to environmental cues, but not to sucrose, reduces sucrose cue reactivity in rats.

In the present study, we examined the effects of extinction of sucrose-predictive contextual cues and/or sucrose satiation on the expression of sucrose cue reactivity in a rat model of relapse. Context extinction was imposed by housing rats in their home cage or in the operant conditioning chamber for 17 h prior to testing. For sucrose satiation, rats were allowed unlimited access to water or sucrose for 17 h prior to testing. Cue reactivity was assessed after either one (Day 1) or 30 (Day 30) days of forced abstinence from sucrose self-administration. An abstinence-dependent increase in sucrose cue reactivity was observed in all conditions ("incubation of craving"). Context extinction dramatically reduced lever responding on both Day 1 and Day 30. Sucrose satiation had no significant effect on cue reactivity in any condition. These results demonstrate that the context in which self-administration occurs maintains a powerful influence over cue reactivity, even after extended forced abstinence. In contrast, the primary reinforcer has little control over cue reactivity. These findings highlight the important role of conditioned contextual cues in driving relapse behavior.

Systemic injection of the DAD1 antagonist SCH 23390 reduces saccharin seeking in rats.

Conditioned cues can elicit drug- and sucrose-seeking behaviors that have been shown to depend on dopamine (DA) D1 receptors. If DAD1 receptors are also involved in seeking behavior in general, blocking these receptors should reduce seeking behavior for a non-caloric, non-drug of abuse reinforcer such as saccharin. Forty-six male Long-Evans rats lever pressed for 0.3% saccharin solution 1 h/day for 10 days. A lever response also activated a tone plus a white stimulus light. This compound stimulus lasted for 5 s. After 1 day of forced abstinence, rats received systemic (0, 1, or 10 µg/kg IP; n = 15-16 per group) injections of SCH 23390 15 min prior to extinction testing. Systemic SCH 23390 reduced saccharin seeking evidenced by a significant reduction in active lever responding and a significant reduction in the number of active lever-contingent deliveries of the tone + light cue following pretreatment with 10 µg/kg SCH 23390. The slope of responding across the Test session in this group was also significantly steeper, indicating that SCH 23390 may have reduced the persistence of saccharin seeking. The results indicate that DAD1 receptors are involved in saccharin seeking and generalize the previously demonstrated anti-seeking effects of DAD1 antagonism to a non-caloric, non-drug of abuse reinforcer.

The dopamine D2 antagonist eticlopride accelerates extinction and delays reacquisition of food self-administration in rats.

Dopamine receptors are implicated in the reinforcing effects of food and drug reinforcement. The purpose of this study was to evaluate whether blocking D2 dopamine receptors during extinction (secondary reinforcement) would affect reacquisition of responding for food pellets (primary reinforcement). Food-restricted rats self-administered (fixed-ratio 1) food pellets in 1-h daily sessions for 7 days. For the next 7 days rats responded in extinction conditions. Before each extinction session rats were injected with saline or the dopamine D2 antagonist eticlopride (0.03 mg/kg, subcutaneously). After the extinction phase, rats were allowed to reacquire food pellet self-administration in seven daily sessions, and received saline or eticlopride before each session. Four treatment groups were represented: saline extinction, saline reacquisition; eticlopride extinction, saline reacquisition; saline extinction, eticlopride reacquisition; and eticlopride extinction, eticlopride reacquisition. Locomotor activity did not differ between eticlopride-treated and saline-treated rats throughout the study. Extinction was accelerated in eticlopride-treated rats. Eticlopride also delayed reacquisition of food self-administration compared with saline-treated rats. Rats administered eticlopride during extinction showed delayed reacquisition and a decreased response rate for food during the reacquisition phase. Indirectly reducing the value of a reinforcer in this way may provide a novel approach for reducing addiction-related food or drug self-administration behaviors.

Nicotine increases sucrose self-administration and seeking in rats.

Associations between nicotine in cigarettes and food consumption may alter the incentive value of food such that food cue-reactivity is exaggerated during abstinence from smoking. This effect may contribute to the weight gain associated with cessation of smoking. We examined the effects of nicotine (0.4 mg/kg base subcutaneous) paired (NPD) or unpaired (NUP) with 10% sucrose self-administration (SA; 0.2 ml/delivery, 1 h/day for 10 days) on SA response rate and intake as well as sucrose cue-reactivity following either 1 or 30 days of forced abstinence. Rats were administered the training dose of nicotine prior to a second, consecutive cue-reactivity session. NPD rats responded at over three times the rate for sucrose and earned nearly twice the number of sucrose deliveries as NUP rats or saline controls. Sucrose cue-reactivity was greater after 30 days versus 1 day of forced abstinence for all groups. History of nicotine exposure had no effect on sucrose cue-reactivity. However, the subsequent injection of nicotine increased sucrose cue-reactivity only in the NPD groups. There were no abstinent-dependent effects of nicotine challenge on sucrose cue-reactivity. A study conducted in parallel with water as the reinforcer revealed a less dramatic effect of nicotine on intake. There was no history or abstinence-dependent effects of nicotine on water cue-reactivity. Nicotine increases the reinforcing effects of sucrose and sucrose-paired cues when nicotine is present. An implication of these findings is that relapse to nicotine (cigarettes) could substantially elevate food cue-reactivity.

Sex differences in sucrose reinforcement in Long-Evans rats.

BACKGROUND: There are sex differences in addiction behaviors. To develop a pre-clinical animal model to investigate this, the present study examined sex differences in sucrose taking and seeking using Long-Evans rats. METHODS: Five experiments were conducted using separate groups of subjects. The first two examined sucrose or saccharin preference in two-bottle home cage choice tests. Experiment three assessed sucrose intake in a binge model with sucrose available in home cage bottles. Experiments four and five utilized operant-based procedures. In experiment four rats responded for sucrose on fixed and progressive ratio (FR, PR) schedules of reinforcement over a range of concentrations of sucrose. A final component of experiment four was measuring seeking in the absence of sucrose challenged with the dopamine D1 receptor antagonist SCH23390. Experiment five assessed responding for water on FR and PR schedules of reinforcement. RESULTS: When accounting for body weight, female rats consumed more sucrose than water; but there was no sex difference in saccharin preference over a range of saccharin concentrations. When accounting for body weight, females consumed more sucrose than males in the binge model, and only females increased binge intake over 14 days of the study. Females responded at higher rates for sucrose under both FR and PR schedules of reinforcement. Females responded at higher rates in extinction (seeking); SCH23390 reduced sucrose seeking of both females and males. Females responded at higher rates for water on FR and PR schedules than males, although rates of responding were low and decreased over sessions. CONCLUSIONS: Across bottle-choice, binge intake, and operant procedures, female Long-Evans rats consumed more sucrose and responded at higher rates for sucrose. Although females also responded more for water, the vigor of responding did not explain the consistent sex difference in sucrose taking and seeking. The sex difference in sucrose taking was also not explained by sweet preference, as there was no sex difference in saccharin preference. These data provide a pre-clinical model to further evaluate sex differences in addiction behaviors and manipulations designed to reduce them.

Factors modulating the incubation of drug and non-drug craving and their clinical implications.

It was suggested in 1986 that cue-induced cocaine craving increases progressively during early abstinence and remains high during extended periods of time. Clinical evidence now supports this hypothesis and that this increase is not specific to cocaine but rather generalize across several drugs of abuse. Investigators have identified an analogous incubation phenomenon in rodents, in which time-dependent increases in cue-induced drug seeking are observed after abstinence from intravenous drug or palatable food self-administration. Incubation of craving is susceptible to variation in magnitude as a function of biological and/or the environmental circumstances surrounding the individual. During the last decade, the neurobiological correlates of the modulatory role of biological (sex, age, genetic factors) and environmental factors (environmental enrichment and physical exercise, sleep architecture, acute and chronic stress, abstinence reinforcement procedures) on incubation of drug craving has been investigated. In this review, we summarized the behavioral procedures adopted, the key underlying neurobiological correlates and clinical implications of these studies.

Incubation of food craving in rats: A review.

Incubation of food craving is an abstinence-dependent increase in responding for reward-paired cues. Incubation of craving was first reported for rats responding for cocaine-paired cues, and later generalized to several drugs of abuse and for food. Incubation of drug and food craving has been reported in clinical studies as well. Incubation of food craving by rats has been reported for standard chow as well as for high fat and sucrose reinforcers. Parametric and other evaluations of the incubation of food craving reveal manipulations that reduce incubation, including environmental enrichment and pharmacological manipulation of dopamine, glutamate, and endogenous opiates. Several brain regions are likely involved in the effect, including mesolimbic terminals and the central nucleus of the amygdala. Further study of the incubation of food craving could facilitate development of treatments for cravings that precede relapse characteristic of drug and food addictions.

Environmental enrichment reduces food seeking and taking in rats: A review.

Environmental enrichment (EE) for rodents is generally defined as providing subjects with an environment enhanced with access to conspecifics, novel and tactile stimuli, and in many preparations, more space. EE exposure, in particular as an "intervention" in adult rodents, decreases food and drug seeking and taking. This review focuses on the reduction of sucrose seeking and taking in rats assessed in operant-based procedures. The operant-based model provides a means to evaluate addiction-related behaviors. Findings using the model might translate to clinically-relevant addiction behaviors directed towards both drugs and food. Both overnight (acute) and one month (chronic) EE effects on behavior are described, including a recent evaluation of the persistence of EE effects following its removal. EE effects on neurobiology related to sucrose seeking using the model are outlined, with a special emphasis on meso-cortico-limbic terminals. Overall, our working hypothesis for how EE reduces sucrose seeking and taking is that EE alters processing of incentive valence. This may also be accompanied by changes in learning and affect. Anti-seeking and anti-taking effects of EE have translational implications for the prevention and treatment of both drug addiction and food-focused behaviors ("food addiction").

Sucrose Abstinence and Environmental Enrichment Effects on Mesocorticolimbic DARPP32 in Rats.

Dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa (DARPP32) is a signaling molecule that could serve as a molecular switch, promoting or restraining sucrose seeking. We measured DARPP32 and pThr34 DARPP32 in the brains of male Long-Evans rats with a history of sucrose self-administration followed by 1 or 30 days of abstinence and exposure to either overnight (acute) or one month (chronic) environmental enrichment (EE). Brains were extracted following a 1 h cue reactivity test or no exposure to the test environment. Micropunches (prelimbic, infralimbic, and anterior cingulate areas of the medial prefrontal cortex, orbitofrontal cortex, dorsal striatum, nucleus accumbens, and ventral tegmental area) were then processed using Western blot. Abstinence increased, while EE decreased, sucrose seeking. DARPP32 and pThr34 DARPP32 levels were affected by testing, abstinence, and/or EE in most regions. Especially salient results were observed in the nucleus accumbens core, a region associated with relapse behaviors. Both acute and chronic EE reduced DARPP32 in the nucleus accumbens core and acute EE increased the ratio of phosphorylated to total DARPP32. Degree of DARPP32 phosphorylation negatively correlated with sucrose seeking. These findings demonstrate a potential role for DARPP32 in mediating the "anti-craving" effect of EE.

Naloxone attenuates incubated sucrose craving in rats.

RATIONALE: Cue-induced craving precedes drug relapse and contributes to eating disorders. Opiate antagonists have been demonstrated to be effective at reducing cravings for drugs and food. Craving, as defined as responding for a stimulus previously associated with a reward, increases, or incubates, over forced abstinence in an animal model of relapse. OBJECTIVES: This paper aims to determine anticraving effects of the opiate antagonist, naloxone, on the incubation of sucrose craving. METHODS: 106 male Long-Evans rats lever pressed for 10% sucrose solution 2 h/day for 10 days. On either day 1 or 30 of forced abstinence, rats responded in extinction for 6 h and then were injected (ip) with either saline or naloxone (0.001, 0.01, 0.1, 1, or 10 mg/kg). The rats then responded for 1 h for presentation of a tone + light cue previously presented with every sucrose delivery during self-administration training. RESULTS: The rats responded more in extinction and following saline on day 30 vs day 1 (an incubation of craving). Except for a trend for a decrease in responding following 10 mg/kg on day 1, naloxone was primarily effective on day 30. On day 30, naloxone significantly reduced responding at all doses except for 0.1 mg/kg. CONCLUSIONS: The time-dependent increase in sensitivity to an opiate antagonist is consistent with time-dependent changes in the opiate system following forced abstinence from sucrose. These changes may partly underlie the incubation of sucrose craving. In addition, these findings could be used to support the use of naloxone as an anticraving medication in protracted abstinence.

Effects of dopamine D1 and D2 receptor agonists on environmental enrichment attenuated sucrose cue reactivity in rats.

RATIONALE: Acute or chronic environmental enrichment (EE) reduces sucrose cue reactivity in rats. This effect may be mediated by dopamine receptors. OBJECTIVES: We examined whether dopamine D1 or D2 receptor agonism could reverse the EE effect. We also examined whether any reversal effects would vary with the incubation of sucrose craving. METHODS: Following 10 days (2 h/day) of sucrose self-administration, rats experienced either 1 or 30 days of forced abstinence and either overnight (acute) or 29 day (chronic) EE. D1 (SKF 81297; 0, 0.3, or 1 mg/kg) or D2 (quinpirole; 0, 0.1, or 0.3 mg/kg) agonist was administered systemically immediately prior to a subsequent 2-h cue reactivity test the next day (n = 9-12 per group). RESULTS: Dose-dependent effects were limited to the day 1 test. High doses of the agonists increased day 1 acute EE cue reactivity to levels comparable to control animals. On the day 30 test, SKF 81297 increased cue reactivity in acute EE, chronic EE, and control rats. In contrast, quinpirole resulted in similar cue reactivity for control and enriched rats, more from a reduction in responding by controls vs. a recovery of responding by EE-experienced rats. CONCLUSIONS: Both D1 and D2 receptors may be involved in the acute EE-mediated decrease in cue reactivity observed following 1 day of forced abstinence. In contrast, at 30 days of forced abstinence, D1 receptors may be critical in cue reactivity as SKF 81297 was effective at both restoring responding of enriched animals and potentiating responding of controls.

Intraventricular insulin and leptin decrease sucrose self-administration in rats.

Data from our laboratory and others have demonstrated an effect of the candidate adiposity signals insulin and leptin to decrease brain reward function, as assessed by lateral hypothalamic self-stimulation and food-conditioned place preference. In this study, we evaluated the effect of centrally administrated insulin or leptin to acutely decrease motivated performance for 5% sucrose, i.e., progressive ratio (PR) sucrose self-administration. Consistent with findings using other behavioral assays, both insulin and leptin significantly decreased the number of bar presses (62+/-7 and 76+/-8% of paired controls respectively), and the number of sucrose rewards obtained (87+/-4 and 91+/-4% of paired controls respectively), relative to within-subjects' control day performance on PR sucrose self-administration, whereas acute intraventricular cerebrospinal fluid had no effect. Rats fed a higher fat diet for 5 weeks were resistant to the effects of the intraventricular insulin or leptin, suggesting a central resistance to their action. Thus the findings of this study extend and support previous observations which suggest that neuroendocrine signals which regulate energy homeostasis in the CNS may also play a role in modulating reward circuitry, and specifically, food reward.

Impact of Environmental Enrichment on Perineuronal Nets in the Prefrontal Cortex following Early and Late Abstinence from Sucrose Self-Administration in Rats.

Perineuronal nets (PNNs) are aggregates of extracellular matrix that form structures surrounding a subset of GABAergic interneurons. The staining intensity of PNNs appears to be related to plasticity. Environmental enrichment (EE) influences plasticity during adulthood: EE decreases the rewarding effects of drugs of abuse and diminishes both drug- and sucrose-seeking behavior. We determined the impact of EE on PNN intensity in the medial prefrontal cortex (mPFC) in rats trained to self-administer sucrose. We examined the number and intensity of PNNs within the prelimbic (PL), infralimbic (IL), and orbitofrontal (OF) regions of the mPFC of adult Long-Evans rats that were trained for sucrose self-administration followed by acute or chronic EE during abstinence and a cue-induced reinstatement test. Rats exposed to EE prior to a cue-induced reinstatement of sucrose seeking had an increase in PNN staining compared with rats in standard housing. Conversely, naïve rats given 1 day of EE had a decrease in PNN intensity in the PL, no change in the IL, and an increase in the OF. Our findings demonstrate that EE increases PNN intensity in the mPFC after sucrose training, suggesting that training enhances the ability of EE to increase PNN intensity. We further demonstrate an interaction between time of abstinence, duration of EE exposure, and cue-induced reinstatement. Our results suggest that increased PNN intensity after EE may alter the excitatory/inhibitory balance of mPFC neurons such that rats are less responsive to a sucrose cue.

Effects of acute or chronic environmental enrichment on regional Fos protein expression following sucrose cue-reactivity testing in rats.

Exposure to environmental enrichment (EE) reduces sucrose seeking by rats with a history of sucrose self-administration. The present experiment examined whether acute or chronic EE also reduces brain Fos levels, a protein marker indicative of neuronal activation. Fos levels were also examined after either 1 or 30 days of forced abstinence to examine whether Fos levels vary with the incubation of sucrose craving. Fos expression was examined in 18 regions and was identified in brain slices using immunohistochemistry. Fos levels were higher in most regions after 30 days of forced abstinence and were decreased in most regions by either acute or chronic EE. Eleven regions had some statistically significant effect and/or interaction of EE or incubation on Fos; the most salient of these are listed here. In the prelimbic cortex, there was an incubation of Fos and EE reduced Fos at both forced abstinence time points. In contrast, in the orbitofrontal cortex, there was no Fos incubation but EE reduced Fos at both forced abstinence time points. An interaction of EE and incubation was observed in the anterior cingulate cortex and nucleus accumbens core and shell where Fos incubated but EE only decreased Fos at the day 30 forced abstinence time point. In contrast, in the dorsolateral striatum Fos incubated, but EE robustly decreased Fos expression at both forced abstinence time points. These differential expression patterns provide rationale for more detailed, site-specific molecular functional studies in how they relate to the ability of EE to reduce sucrose seeking.

Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving.

Using a rat model of drug craving, we found that the responsiveness to cocaine cues progressively increases or incubates over the first 60 d of cocaine withdrawal. Here we studied whether alterations in brain-derived neurotrophic factor (BDNF) protein levels within the mesolimbic dopamine system are associated with this incubation phenomenon. BDNF is involved in synaptic plasticity and was found to enhance responding for cues associated with natural rewards. Rats were trained to press a lever to receive intravenous cocaine or oral sucrose for 6 hr/d for 10 d; each earned reward was paired with a tone-light cue. Resumption of lever-pressing behavior was then assessed on days 1, 30, or 90 of reward withdrawal. First, resistance to extinction was assessed during 6 hr in which lever presses were not reinforced and the cue was absent. Second, cue-induced reinstatement was assessed after extinction during 1 hr in which responding led to cue presentations. Other rats were killed without testing on days 1, 30, and 90 of reward withdrawal, and BDNF and nerve growth factor (NGF) protein levels were measured in the ventral tegmental area (VTA), accumbens, and amygdala. Lever pressing during extinction and cue-induced reinstatement tests of cocaine craving progressively increased after cocaine withdrawal. Time-dependent changes also were observed during the tests for sucrose craving, with maximal responding on day 30. BDNF, but not NGF, levels in the VTA, accumbens, and amygdala progressively increased after cocaine, but not sucrose, withdrawal. Time-dependent increases in BDNF levels may lead to synaptic modifications that underlie enhanced responsiveness to cocaine cues after prolonged withdrawal periods.

Incubation of sucrose craving: effects of reduced training and sucrose pre-loading.

Time-dependent increases in cue-induced reward seeking after forced abstinence were described in rats with a history of cocaine or sucrose self-administration, suggesting reward craving incubates over time. In the present study, we examined the effects of reduced training experience, or sucrose pre-loading just prior to testing, on the incubation of sucrose craving. Sucrose seeking (responding in extinction and then for a sucrose-paired cue) increased over time in groups of rats that self-administered sucrose 6 h/day for 10 days and were tested at 1, 7, or 30 days of forced abstinence. We found that groups of rats that had self-administered 2 instead of 6 h/day showed a similar profile of responding. Incubation of sucrose craving was attenuated by free access to sucrose in home cages for 17 h immediately prior to testing assessed as extinction responding on days 1 and 30. However, this sucrose pre-loading had no effect on the time-dependent increase in responding for the sucrose-paired cue. In summary, reducing the training experience had no effect on the incubation of sucrose craving and free access to sucrose had only a limited effect-attenuating extinction responding. These results illustrate the strength of the incubation of craving and further suggest long-term changes in brain motivational circuitry following sucrose self-administration.

Effect of dopamine receptor antagonists on renewal of cocaine seeking by reexposure to drug-associated contextual cues.

We recently found that in rats trained to self-administer a heroin-cocaine mixture, exposure to the drug self-administration environment, after extinction of the drug-reinforced behavior in a different context, leads to renewal of drug seeking. Here we further explored the role of contextual stimuli in drug seeking by characterizing the effect of drug-associated environmental stimuli on renewal of cocaine seeking. We also investigated whether activation of dopamine receptors contributes to context-induced renewal of cocaine seeking by testing the effects of selective D1-like (SCH 23390) and D2-like (raclopride) receptor antagonists. Rats were trained for 10 days to self-administer cocaine by pressing a lever. Next, lever pressing was extinguished in the presence of the discrete cues associated with cocaine infusions for 10 days in a context that was distinctively different from the drug-taking context. On the test days, rats were pretreated with SCH 23390 (0, 5 or 10 microg/kg) or raclopride (0, 50 or 100 microg/kg) and non-reinforced lever-pressing behavior was determined either in the extinction context (Control group) or the cocaine-associated context (Renewal group). Consistent with our previous report, cocaine seeking was renewed when rats were exposed to the drug-associated context after extinction in a different context. Furthermore, pretreatment with the D1-like or the D2-like receptor antagonists attenuated context-induced renewal of cocaine seeking. These data suggest that activation of dopamine receptors is involved in reinstatement of cocaine seeking induced by exposure to the drug self-administration context.

Incubation of cocaine craving after withdrawal: a review of preclinical data.

Using a rat model of drug craving and relapse, we recently found that cocaine seeking induced by re-exposure to drug-associated cues progressively increases over the first 2 months after withdrawal from cocaine self-administration, suggesting that drug craving incubates over time [Nature 412 (2001) 141]. Here, we summarize data from studies that further characterized this incubation phenomenon and briefly discuss its implications for drug addiction. The main findings of our ongoing research are: 1. Incubation of cocaine craving is long-lasting, but not permanent: cocaine seeking induced by exposure to cocaine cues remains elevated for up to 3 months of withdrawal, but decreases after 6 months. 2. Incubation of reward craving is not drug specific: sucrose seeking induced by re-exposure to the reward cues also increases after withdrawal, but for a time period that is shorter than that of cocaine. 3. Incubation of cocaine craving is not evident after acute re-exposure to cocaine itself: cocaine seeking induced by cocaine priming injections remains essentially unchanged over the first 6 months of withdrawal. 4. Incubation of cocaine craving after withdrawal is associated with increases in the levels of brain-derived neurotrophic factor (BDNF) in mesolimbic dopamine areas.