Neurobiology of the incubation of drug craving

Abstract

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 past 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 understanding of brain mechanisms and circuits that underlie craving and relapse in human addicts.

Figure 1. Incubation of reward craving

Extinction tests: Data are mean (±SEM) number of non-reinforced responses on a lever previously paired with reward delivery during self-administration at different days after withdrawal from (A) cocaine (left panel, [4]; right panel, [18]), (B) heroin [left panel, [6], right panel, [86]), (C) nicotine [9], (D) alcohol [8], (E) methamphetamine [7], or (F) oral sucrose [109]. During the extinction tests in [6, 7, 18, 86, 109], rats were re-exposed to the reward-associated environment (i.e., the self-administration chambers) and lever presses led to contingent presentations of a discrete cue previously paired with reward delivery. During the extinction tests in [4, 8, 9], rats were re-exposed to the self-administration chambers and lever presses had no reinforced consequences. * Different from withdrawal day 1, p<0.05. Data were redrawn, with permission, from the above cited references.

Figure 2. Brain regions and molecular mechanisms involved in incubation of cocaine craving

Horizontal section of a rat brain [116] depicting the mesocorticolimbic (red arrows) and nigrostriatal (red dashed arrows) dopamine systems and the glutamatergic projections (green arrows) to the NAc. The depicted mechanisms, which are summarized in detail in the text, refer to the roles in incubation of cocaine craving of ventral mPFC (vmPFC) neuronal activity [54], GluA2-lacking AMPARs in the NAc [–91], BDNF signaling in the NAc and VTA [20, 79, 80], GDNF activity in the VTA [85], and CeA ERK activity and glutamate transmission [68, 69]. Abbreviations: BLA and CeA, basolateral and central nuclei of the amygdala; BNST, bed nucleus of the stria terminalis: DH, dorsal hippocampus; DLS, dorsolateral striatum; dmPFC and vmPFC, dorsal and ventral medial prefrontal cortex; SNA, substantia nigra; VH, ventral hippocampus; VP, ventral pallidum.

Figure 3. A putative signaling cascade involving the activation of ERK through GDNF and BDNF signaling in the VTA and its importance to the incubation of cocaine craving

Increased secreted GDNF can increase ERK activity via its actions on RET tyrosine kinase/glial cell line-derived receptor alpha 1 (GFRα1) [117] or GFRα1/neural cell adhesion molecule (NCAM) [118] signaling mechanisms. Increased extracellular BDNF can increase ERK activity via its actions on the TrkB neurotrophin receptor [63]. Increased ERK phosphorylation can activate transcription factors like CREB and immediate early genes (IEG) like c-fos and Egr1 that play a role in BDNF- and GDNF-induced long-term neuroadaptations that potentially contribute to the incubation of cocaine craving.

Figure 4. Physiological differences between GluA2-lacking and GluA2-containing AMPARs in the brain and their relevance for incubation of cocaine craving

GluA2-lacking AMPARs differ from GluA2-containing AMPARs in several physiological characteristics, including channel conductance, permeability to calcium ions, and inward rectification [87, 88]. The formation of GluA2-lacking AMPARs has been observed in the NAc after prolonged withdrawal from cocaine (reviewed in [89]). The synaptic incorporation of these new receptors can enhance the responsiveness of NAc neurons to glutamatergic inputs from cortical and limbic regions, due to both the increases in the absolute number of surface AMPARs and the higher conductance of GluA2-lacking AMPARs [90]. As discussed in the text, there is evidence that these newly formed GluA2-lacking AMPARs in the NAc play a critical role in the incubation of cocaine craving.