Exposure to drugs of abuse causes dysfunction of nucleus accumbens (NAc) neurons, which are strongly linked to motivation and addiction. Despite the estimate that an enormous number of drug-induced effects represent homeostatic responses, drug-induced homeostatic regulation and dysregulation in the NAc have not been well characterized. This application will explore the contribution of homeostatic plasticity to cue induced cocaine craving. More specifically, it has been observed that cues associated with prior cocaine use are powerful triggers of relapse in abstinent cocaine users and of drug seeking in cocaine-experienced rodents. This cue-induced cocaine craving progressively intensifies (incubates) over the course of withdrawal from extended access cocaine self-administration. Growing evidence supports the relevance of incubation to drug craving in humans. A key feature of the incubation process is that, once initiated, it continues to exacerbate automatically during the withdrawal period, without apparent external stimulation. This suggests the involvement of homeostatic rather than Hebbian forms of neuronal plasticity. Using rats, we propose to determine the role of homeostatic plasticity in the NAc in the incubation of cocaine craving. Homeostatic plasticity is a physiological self-correcting mechanism through which neurons compensate for 'undesirable'cellular alterations, thus stabilizing their functional output Are there any forms of homeostatic regulation/dysregulation in NAc neurons that may be involved in incubation of craving? We previously demonstrated a form of homeostatic crosstalk between excitatory synaptic input and intrinsic membrane excitability in NAc neurons. This phenomenon, termed homeostatic synapse-membrane crosstalk (HSMC), enables NAc neurons to adjust their intrinsic membrane excitability to functionally offset alterations in excitatory synaptic strength. As a consequence, the optimal output of NAc neurons may be stably maintained. However, if misled by "false" homeostatic signals, HSMC may be erroneously engaged, triggering cascades of homeostatic dysregulation that progressively shift neuronal output further and further from the normal set-point. Our central hypothesis, based on extensive preliminary results, is that increased transmission via NR2B-containing NMDARs constitutes a "false" homeostatic signal that triggers HSMC and subsequent homeostatic dysregulation cascades, ultimately resulting in a persistent decrease in membrane excitability and an increase in synaptic strength. Together, these changes are hypothesized to magnify the response of NAc neurons to cocaine-associated cues and thereby contribute to incubation of cocaine craving. To test this hypothesis, this proposal will characterize key molecular substrates for HSMC-based dysregulation cascades and test the ability of HSMC-based approaches to attenuate incubation of cocaine craving. We will use a multidisciplinary approach combining in vivo molecular/pharmacological manipulations, biochemistry, slice electrophysiology, and behavioral tests. Our results will set the stage for translational studies aimed at developing a homeostasis-based pharmacological strategy to restore normal NAc function in cocaine users.

Public Health Relevance

Exposure to cocaine or other drugs of abuse induces a large number of molecular and cellular adaptations, many of which are thought to be homeostatic, but their cellular and behavioral consequences remain unclear. This application will test the hypothesis that some of these cocaine-induced cellular adaptations trigger a homeostatic dysregulation cascade in the nucleus accumbens, leading to progressive intensification of cocaine craving. Our results may provide a new conceptual basis to understand and treat cocaine addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Special Emphasis Panel (ZRG1-MDCN-B (04))
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Sorensen, Roger
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University of Pittsburgh
Schools of Arts and Sciences
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Dong, Yan; Nestler, Eric J (2014) The neural rejuvenation hypothesis of cocaine addiction. Trends Pharmacol Sci 35:374-83
Ma, Yao-Ying; Lee, Brian R; Wang, Xiusong et al. (2014) Bidirectional modulation of incubation of cocaine craving by silent synapse-based remodeling of prefrontal cortex to accumbens projections. Neuron 83:1453-67
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Ishikawa, Masago; Otaka, Mami; Neumann, Peter A et al. (2013) Exposure to cocaine regulates inhibitory synaptic transmission from the ventral tegmental area to the nucleus accumbens. J Physiol 591:4827-41
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Lee, Brian R; Ma, Yao-Ying; Huang, Yanhua H et al. (2013) Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving. Nat Neurosci 16:1644-51