Neurobiology of the incubation of drug craving

Pickens, Charles L.; Airavaara, Mikko; Theberge, Florence; Fanous, Sanya; Hope, Bruce T.; Shaham, Yavin

doi:10.1016/j.tins.2011.06.001

Cited by 571 publications

(524 citation statements)

References 115 publications

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“…These are studies that cannot be performed or are very difficult to perform in mice. For example, our retro-DREADD method is ideally suitable for circuitry-related studies using long-term intravenous drug self-administration procedures (Schuster and Thompson, 1969) and animal models of drug relapse and craving (Shaham et al, 2003;Pickens et al, 2011) that are technically challenging in mice.…”

Section: Discussionmentioning

confidence: 99%

Behavioral and Physiological Effects of a Novel Kappa-Opioid Receptor-Based DREADD in Rats

Marchant

Whitaker²,

Bossert³

et al. 2015

Neuropsychopharmacol

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In the past decade, novel methods using engineered receptors have enabled researchers to manipulate neuronal activity with increased spatial and temporal specificity. One widely used chemogenetic method in mice and rats is the DREADD (designer receptors exclusively activated by designer drugs) system in which a mutated muscarinic G protein-coupled receptor is activated by an otherwise inert synthetic ligand, clozapine-N-oxide (CNO). Recently, the Roth laboratory developed a novel inhibitory DREADD in which a mutated kappa-opioid receptor (KORD) is activated by the pharmacologically inert drug salvinorin B (SalB; Vardy et al, 2015). They demonstrated the feasibility of using KORD to study brain circuits involved in motivated behavior in mice. Here, we used behavioral, electrophysiological, and neuroanatomical methods to demonstrate the feasibility of using the novel KORD to study brain circuits involved in motivated behavior in rats. In Exp. 1, we show that SalB dose-dependently decreased spontaneous and cocaine-induced locomotor activity in rats expressing KORD to midbrain (ventral tegmental area/substantia nigra). In Exp. 2, we show that SalB completely inhibited tonic firing in KORDexpressing putative dopamine neurons in midbrain. In Exp. 3, we used a 'retro-DREADD' dual-virus approach to restrict expression of KORD in ventral subiculum neurons that project to nucleus accumbens shell. We show that KORD activation selectively decreased novel context-induced Fos expression in this projection. Our results indicate that the novel KORD is a promising tool to selectively inactivate brain areas and neural circuits in rat studies of motivated behavior.

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Section: Discussionmentioning

confidence: 99%

Behavioral and Physiological Effects of a Novel Kappa-Opioid Receptor-Based DREADD in Rats

Marchant

Whitaker²,

Bossert³

et al. 2015

Neuropsychopharmacol

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“…On withdrawal day (WD) 1 or after prolonged withdrawal (WD50-60; see next section for justification of this withdrawal period), we induced memory retrieval and assessed cue-induced cocaine-seeking by returning animals to the operant chambers for a 30-min test (Figure 1b). During the test, nose-pokes in the previously active hole (the operational measure of cue-induced craving in incubation of craving studies; Lu et al, 2004;Pickens et al, 2011) delivered the light cue but no cocaine infusion. Two-way ANOVA revealed a significant interaction of treatment and WD (F (2,51) = 4.98, Po0.05).…”

Section: Behavioral Data and Tissue Preparationmentioning

confidence: 99%

“…To address these issues, we measured UPS activation upon retrieval of cocaine memories after an extended-access cocaine self-administration paradigm that leads to progressive intensification, or 'incubation', of cue-induced craving over the first months of withdrawal (Lu et al, 2004;Pickens et al, 2011). We compared UPS activation at early and late withdrawal times, when craving is low and high, respectively, in order to assess its relationship both to the age of the memory and the intensity of craving.…”

Section: Introductionmentioning

confidence: 99%

Response of the Ubiquitin-Proteasome System to Memory Retrieval After Extended-Access Cocaine or Saline Self-Administration

Werner

Milovanovic

Christian

et al. 2015

Neuropsychopharmacol

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The ubiquitin-proteasome system (UPS) has been implicated in the retrieval-induced destabilization of cocaine-and fear-related memories in Pavlovian paradigms. However, nothing is known about its role in memory retrieval after self-administration of cocaine, an operant paradigm, or how the length of withdrawal from cocaine may influence retrieval mechanisms. Here, we examined UPS activity after an extended-access cocaine self-administration regimen that leads to withdrawal-dependent incubation of cue-induced cocaine craving. Controls self-administered saline. In initial experiments, memory retrieval was elicited via a cue-induced seeking/retrieval test on withdrawal day (WD) 50-60, when craving has incubated. We found that retrieval of cocaine-and saline-associated memories produced similar increases in polyubiquitinated proteins in the nucleus accumbens (NAc), compared with rats that did not undergo a seeking/retrieval test. Measures of proteasome catalytic activity confirmed similar activation of the UPS after retrieval of saline and cocaine memories. However, in a subsequent experiment in which testing was conducted on WD1, proteasome activity in the NAc was greater after retrieval of cocaine memory than saline memory. Analysis of other brain regions confirmed that effects of cocaine memory retrieval on proteasome activity, relative to saline memory retrieval, depend on withdrawal time. These results, combined with prior studies, suggest that the relationship between UPS activity and memory retrieval depends on training paradigm, brain region, and time elapsed between training and retrieval. The observation that mechanisms underlying cocaine memory retrieval change depending on the age of the memory has implications for development of memory destabilization therapies for cue-induced relapse in cocaine addicts.

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“…Despite this disagreement, the importance of pavlovian associations with craving was recognized from the very beginning (Wikler, 1948). It is now accepted that drug-associated stimuli evoke drug memories, triggering craving and relapse (Robinson and Berridge, 1993;Robbins et al, 2008;Pickens et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

The cerebellum in drug craving

Moreno-Rius

Miquel

2017

Drug and Alcohol Dependence

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Craving has been considered one of the core features of addiction. It can be defined as the urge or conscious desire to use a drug elicited by the drug itself, drug-associated cues or stressors. Craving plays a major role in relapse, even after prolonged periods of abstinence, as well as in the maintenance of drug seeking in non-abstinent addicts. The circuitry of craving includes medial parts of the prefrontal cortex, ventral striatal zones, ventral tegmental area, ventral pallidum, and limbic regions. Interestingly, the cerebellum shows reciprocal loops with many of these areas. The cerebellum has been linked traditionally to motor functions but increasing evidence indicates that this part of the brain is also involved in functions related to cognition, prediction, learning, and memory. Moreover, the functional neuroimaging studies that have addressed the study of craving in humans repeatedly demonstrate cerebellar activation when craving is elicited by the presentation of drug-related cues. However, the role of cerebellar activity in these craving episodes remains unknown. Therefore, the main goal of this review is to provide a brief update on craving studies and the traditional neural basis of this phenomenon, and then discuss and propose a hypothesis for the function of the cerebellum in craving episodes.

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Neurobiology of the incubation of drug craving

Cited by 571 publications

References 115 publications

Behavioral and Physiological Effects of a Novel Kappa-Opioid Receptor-Based DREADD in Rats

Behavioral and Physiological Effects of a Novel Kappa-Opioid Receptor-Based DREADD in Rats

Response of the Ubiquitin-Proteasome System to Memory Retrieval After Extended-Access Cocaine or Saline Self-Administration

The cerebellum in drug craving

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