Cues associated with prior cocaine use are powerful triggers of relapse in abstinent cocaine users and of drug seeking in cocaine-experienced rodents. Rodent studies show that cue-induced cocaine craving progressively intensifies over the course of withdrawal from extended access cocaine self-administration. This phenomenon, known as incubation of cocaine craving, may contribute to the difficulty of maintaining abstinence from cocaine use. 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 a mouse model, this proposal aims to determine the role of homeostatic plasticity in the nucleus accumbens (NAc), a key brain region for addiction, in the incubation of cocaine craving. Ho- meostatic plasticity is a physiological self-correcting mechanism through which neurons compensate for 'unde- sirable'cellular alterations, thus stabilizing their functional output. Are there any forms of homeostatic neural plasticity in NAc neurons that may help these neurons regain normal function following cocaine exposure? We previously demonstrated a form of homeostatic crosstalk between excitatory synaptic input and intrinsic mem- brane 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. In previous work, we showed that cocaine exposure increases synaptic levels of NR2B-containing NMDA re- ceptors in the NAc. Our central hypothesis, based on extensive preliminary results, is that this 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 the- reby elicit incubation of cocaine craving. To test this hypothesis, this proposal will characterize key molecular substrates for HSMC-based dysregulation cascades (e.g., glutamate receptors and SK-type potassium chan- nels), examine the role of dopamine in modulating these cascades, and develop a HSMC-based approach to attenuate incubation of cocaine craving. To achieve these goals, we will use a multidisciplinary approach com- bining 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 pharma- cological strategy to restore normal NAc function in cocaine users.
Homeostatic plasticity in addiction-related brain regions and its role in drug-induced cellular adaptations remain underexplored. Using homeostatic synapse-membrane crosstalk as a mechanistic model, we propose to identify a cellular basis underlying drug-induced homeostatic dysregulation that mediates the incubation of cocaine craving.
|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|
|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|
|Chen, Bo; Ma, Yao-Ying; Wang, Yao et al. (2013) Cocaine-induced membrane adaptation in the central nucleus of amygdala. Neuropsychopharmacology 38:2240-8|
|Bonnet, Stephanie A D; Akad, Derya S; Samaddar, Tanmoy et al. (2013) Synaptic state-dependent functional interplay between postsynaptic density-95 and synapse-associated protein 102. J Neurosci 33:13398-409|
|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|
|Huang, Yanhua H; Schluter, Oliver M; Dong, Yan (2013) An unusual suspect in cocaine addiction. Neuron 80:835-6|