It was suggested in 1986 that cue-induced drug craving in cocaine addicts progressively increases over the first several weeks of abstinence and remains high for extended periods. During the last decade, investigators have identified an analogous incubation phenomenon in rodents, in which time-dependent increases in cue-induced drug seeking are observed after withdrawal from intravenous cocaine self-administration. Such an incubation of drug craving is not specific to cocaine, as similar findings have been observed after self-administration of heroin, nicotine, methamphetamine, and alcohol in rats. In this review, we discuss recent results that have identified important brain regions involved in the incubation of drug craving, as well as evidence for the underlying cellular mechanisms. Understanding the neurobiology of the incubation of drug craving in rodents is likely to have significant implications for furthering our understanding of brain mechanisms and circuits that underlie drug craving in human addicts.

The orbitofrontal cortex (OFC) and basolateral amygdala (BLA) are critical for using learned representations of outcomes to guide behavior. Neurophysiological findings suggest complementary roles in which the BLA acquires associations between cues and outcomes and the OFC subsequently uses them to guide behavior. Here, we have used a reinforcer devaluation paradigm to test this hypothesis. In this paradigm, rats are first trained to associate a light conditioned stimulus (CS) with a food outcome, and then the food is devalued by pairing it with illness. After this devaluation procedure, responding to the CS is assessed in a single probe session. Previously, we have shown that BLA and OFC lesions made before training do not affect the acquisition of conditioned responding but do impair the sensitivity of that responding to reinforcer devaluation. Rats with such lesions fail to exhibit the spontaneous decrease in conditioned responding to the light cue observed in controls in the probe test. Here, we have extended those findings by showing that performance in the probe test is impaired by OFC lesions made after light-food conditioning but not by BLA lesions made after that training. These findings indicate that the OFC and BLA play different roles in mediating normal goal-directed performance in this, and likely other, settings. The BLA seems critical to forming representations linking cues to the incentive properties of outcomes but not for maintaining these representations in memory, updating them with new information, or for expressing them in behavior. In contrast, the OFC seems essential for one or more of these latter processes.

Drug addictions including alcoholism are characterized by degradation of executive control over behavior and increased compulsive drug seeking. These profound behavioral changes are hypothesized to involve a shift in the regulation of behavior from prefrontal cortex to dorsal striatum (DLS). Studies in rodents have shown that ethanol disrupts cognitive processes mediated by the prefrontal cortex, but the potential effects of chronic ethanol on DLS-mediated cognition and learning are much less well understood. Here, we first examined the effects of chronic EtOH on DLS neuronal morphology, synaptic plasticity, and endocannabinoid-CB1R signaling. We next tested for ethanol-induced changes in striatal-related learning and DLS in vivo single-unit activity during learning. Mice exposed to chronic intermittent ethanol (CIE) vapor exhibited expansion of dendritic material in DLS neurons. Following CIE, DLS endocannabinoid CB1 receptor signaling was down-regulated, and CB1 receptordependent long-term depression at DLS synapses was absent. CIE mice showed facilitation of DLS-dependent pairwise visual discrimination and reversal learning, relative to air-exposed controls. CIE mice were also quicker to extinguish a stimulus-reward instrumental response and faster to reduce Pavlovian approach behavior under an omission schedule. In vivo single-unit recording during learning revealed that CIE mice had augmented DLS neuronal activity during correct responses. Collectively, these findings support a model in which chronic ethanol causes neuroadaptations in the DLS that prime for greater DLS control over learning. The shift to striatal dominance over behavior may be a critical step in the progression of alcoholism.lcoholism is a highly prevalent disorder with a massive and growing impact on public health (1). The course of alcoholism and other chronic drug addictions has been conceptualized as involving the progressive deterioration of executive control of behavior and the corresponding emergence of compulsive drug seeking (2, 3). At the neural systems level, this shift is associated with a "devolution" away from prefrontal cortical (PFC) regulation of behavior in favor of greater control by subcortical regions including the dorsal striatum (DS) (2, 4).Consistent with this scheme, alcohol-dependent individuals show impairments on PFC-mediated cognitive measures, such as impulse control and reversal learning (5, 6), but exaggerated neural responses in the DS when, for example, presented with alcohol-associated cues (7-9). Along similar lines, rodents chronically exposed to ethanol (EtOH) exhibit deficits in PFC-and hippocampal-mediated tasks, including spatial and reversal learning, set-shifting, and fear extinction, that in some cases are linked to cortical cell death (10-17).These observations are consistent with an EtOH-induced impairment in various PFC-related cognitive behaviors but do not address the possibility of concomitant changes in processes mediated by the DS. In this context, recent studies in rats have found that ch...

The orbitofrontal cortex (OFC) has been implicated in the use of outcome expectancies to guide behavior. The present study used a devaluation task to examine this function. Rats first received light-food pairings followed by food-toxin pairings designed to devalue the food. After either excitotoxic or sham OFC lesions, responding to the light was reassessed. Sham-lesioned rats showed reduced responding to the light relative to behavioral controls, which had received food and toxin unpaired. In contrast, OFC-lesioned rats showed no such reductions. Combined with previous data (C. L. Pickens, M. P. Saddoris, B. Setlow, M. Gallagher, P. C. Holland, & G. Schoenbaum, 2003), these results indicate that the OFC is critical for the maintenance of information about the current incentive value of reinforcers or the use of that information to guide behavior.

Background Conditioned fear memories can be updated by extinction during reconsolidation, and this effect is specific to the reactivated conditioned stimulus (CS). However, a traumatic event can be associated with several cues, and each cue can potentially trigger recollection of the event. In the present study, we introduced a technique to target all diverse cues associated with an aversive event that causes fear. Methods In the human experiments, the subjects underwent modified fear conditioning, in which they were exposed to an unconditioned stimulus (US) or unreinforced CS to reactivate the memory and then underwent extinction, spontaneous recovery, and reinstatement. In the animal experiments, rats underwent contextual fear conditioning under a similar protocol as the used in the human experiments. We also explored the molecular alterations after US reactivation in rats. Results We found that presentation of a lower-intensity US following extinction disrupted the associations between the different CSs and reactivated US in both humans and rats. This disruptive effect persisted for at least 6 months in humans and was selective to the reactivated US. This procedure was also effective for remote memories in both humans and rats. Compared with the CS, the US induced stronger endocytosis of AMPA glutamate receptors 1 and 2 and stronger activation of protein kinase A, p70S6 kinase, and cyclic adenosine monophosphate response element binding protein in the dorsal hippocampus in rats. Conclusions These findings demonstrate that a modified US retrieval-extinction strategy may have a potential impact on therapeutic approaches to prevent the return of fear.