Incubation of cocaine craving after withdrawal

The cocaine-addicted phenotype can be modeled in rats based on individual differences in preferred levels of cocaine intake and a propensity for relapse in withdrawal. These cocaine-taking and -seeking behaviors are strongly but differentially regulated by postsynaptic D 1 and D 2 receptors in the mesolimbic dopamine system. Thus, we determined whether addiction-related differences in cocaine selfadministration would be related to differential sensitivity in functional D 1 and D 2 receptor responses. Using a population of 40 outbred Sprague-Dawley rats trained to self-administer cocaine for 3 weeks, we found that animals with higher preferred levels of cocaine intake exhibited a vertical and rightward shift in the self-administration dose-response function, and were more resistant to extinction from cocaine self-administration, similar to phenotypic changes reported in other models of cocaine addiction. After 3 weeks of withdrawal from cocaine self-administration, high intake rats were subsensitive to the ability of the D 1 agonist SKF 81297 to inhibit cocaine-seeking behavior elicited by cocaine priming, but supersensitive to cocaine seeking triggered by the D 2 agonist quinpirole, when compared to low intake rats. Additionally, high intake rats developed profound increases in locomotor responses to D 2 receptor challenge from early to late withdrawal times, whereas low intake rats developed increased responsiveness to D 1 receptor challenge. In a second experiment, responses to the mixed D 1 /D 2 agonist apomorphine and the NMDA glutamate receptor antagonist MK-801 failed to differ between low and high intake rats. These findings suggest that cocaine addiction is related specifically to differential alterations in functional D 1 and D 2 receptors and their ability to modulate cocaine-seeking behavior.

Section: Brain Cocaine Levelsmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Addiction-Related Alterations in D1 and D2 Dopamine Receptor Behavioral Responses Following Chronic Cocaine Self-Administration

Edwards

Whisler

Fuller

et al. 2006

“…A possible explanation for these effects could be focused on the fact that MDMA may produce a transient depletion of one or several neurotransmitters involved in the expression of CPP, such as 5-HT or DA. On the other hand, the phenomenon of 'incubation' of responding to reward cues (Grimm et al, 2001;Lu et al, 2004) could also contribute to the increased CPP over time following the completion of training, it becoming more evident 1 or several weeks after the last conditioning session (extinction sessions) than only 1 day after (Post-C). The effects of MDMA on CPP have always been evaluated using a schedule of alternating days.…”

Section: Effects Of Daily and Alternating Mdma Administration On The mentioning

confidence: 99%

Rewarding Effects and Reinstatement of MDMA-Induced CPP in Adolescent Mice

Daza-Losada

Couto

Manzanedo

et al. 2007

Although the rewarding effects of 3,4-methylenedioxy-metamphetamine (MDMA) have been demonstrated in self-administration and conditioned place preference (CPP) procedures, its addictive potential (ie, the vulnerability to relapse, measured by its ability to induce reinstatement of an extinguished response), remains poorly understood. In this study, the effects of MDMA (5, 10, and 20 mg/kg) on the acquisition, extinction and reinstatement of CPP were evaluated in mice, using two different protocols during acquisition of CPP. In the first experiment, animals were trained using a two-session/day schedule (MDMA and saline for 4 consecutive days), whereas in the second experiment, they were trained using an alternating day schedule (MDMA and saline each 48 h). After extinction, the ability of drug priming to reinstate CPP was evaluated. In Experiment 1, MDMA did not significantly increase the time spent in the drug-paired compartment during the post-conditioning (Post-C) test, although the preference was evident a week afterwards, lasting between 2 and 21 weeks. No reinstatement was observed after MDMA priming. In Experiment 2, all doses produced CPP in Post-C, which lasted between 1 and 4 weeks. MDMA induces reinstatement at doses up to 4 times lower than those used in conditioning. The analyses of brain monoamines revealed that the daily schedule of treatment induces a non-dose-dependent decrease in dopamine and serotonin (5-HT) in the striatum, whereas the alternating schedule produces a dose-dependent decrease of 5-HT in the cortex. These results demonstrate that MDMA produces long-lasting rewarding effects and reinstatement after extinction, suggesting the susceptibility of this drug to induce addiction.

“…Work by Shaham, Hope, and colleagues has addressed this issue in a number of studies of incubation (reviewed in Lu et al, 2004;Shaham and Hope, 2005). In cocaine selfadministering rats, increased responding on the previously active lever was evident after 7 or more days of cocaine abstinence (Grimm et al, 2001). This phenomenon is incubation, and further studies demonstrated that persis-tent changes in mesolimbic (Lu et al, 2003) and amygdalar (Lu et al, 2005a) protein expression accompanied the behavioral change.…”

Section: Introductionmentioning

confidence: 99%

Persistent Alterations in Mesolimbic Gene Expression with Abstinence from Cocaine Self-Administration

Freeman

Patel

Brucklacher

et al. 2007

108

126

Cocaine-responsive gene expression changes have been described after either no drug abstinence or short periods of abstinence. Little data exist on the persistence of these changes after long-term abstinence. Previously, we reported that after discrete-trial cocaine selfadministration and 10 days of forced abstinence, incubation of cocaine reinforcement was observable by a progressive ratio schedule. The present study used rat discrete-trial cocaine self-administration and long-term forced abstinence to examine extinction responding, mRNA abundance of known cocaine-responsive genes, and chromatin remodeling. At 30 and 100 days of abstinence, extinction responding increased compared to 3-day abstinent rats. Decreases in both medial prefrontal cortex (mPFC) and nucleus accumbens cfos, Nr4a1, Arc, and EGR1 mRNA were observed, and in most cases persisted, for 100 days of abstinence. The signaling peptides CART and neuropeptide Y (NPY) transiently increased in the mPFC, but returned to baseline levels following 10 days of abstinence. To investigate a potential regulatory mechanism for these persistent mRNA changes, levels of histone H3 acetylation at promoters for genes with altered mRNA expression were examined. In the mPFC, histone H3 acetylation decreased after 1 and 10 days of abstinence at the promoter for EGR1. H3 acetylation increased for NPY after 1 day of abstinence and returned to control levels by 10 days of abstinence.Behaviorally, these results demonstrate incubation after discrete-trial cocaine self-administration and prolonged forced abstinence. This incubation is accompanied by changes in gene expression that persist long after cessation of drug administration and may be regulated by chromatin remodeling.