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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA030379-02
Application #
8651907
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Sorensen, Roger
Project Start
2013-04-15
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$426,897
Indirect Cost
$79,929
Name
University of Pittsburgh
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Wright, William J; Schl├╝ter, Oliver M; Dong, Yan (2017) A Feedforward Inhibitory Circuit Mediated by CB1-Expressing Fast-Spiking Interneurons in the Nucleus Accumbens. Neuropsychopharmacology 42:1146-1156
Wright, William J; Dong, Yan (2017) Tipping the Scales Toward Addiction. Biol Psychiatry 81:903-904
Wright, William J; Dong, Yan (2017) Intrinsic Excitability of Cocaine-Associated Memories. Neuropsychopharmacology :
Liu, Zheng; Wang, Yao; Cai, Li et al. (2016) Prefrontal Cortex to Accumbens Projections in Sleep Regulation of Reward. J Neurosci 36:7897-910
Ma, Yao-Ying; Wang, Xiusong; Huang, Yanhua et al. (2016) Re-silencing of silent synapses unmasks anti-relapse effects of environmental enrichment. Proc Natl Acad Sci U S A 113:5089-94
Neumann, Peter A; Wang, Yicun; Yan, Yijin et al. (2016) Cocaine-Induced Synaptic Alterations in Thalamus to Nucleus Accumbens Projection. Neuropsychopharmacology 41:2399-410
Wright, William J; Dong, Yan (2016) N-Methyl-D-Aspartate Receptors: ""C""ing the Culprits Behind Cocaine-Induced Metaplasticity. Biol Psychiatry 80:644-646
Dong, Yan (2016) Silent Synapse-Based Circuitry Remodeling in Drug Addiction. Int J Neuropsychopharmacol 19:
Graziane, Nicholas M; Sun, Shichao; Wright, William J et al. (2016) Opposing mechanisms mediate morphine- and cocaine-induced generation of silent synapses. Nat Neurosci 19:915-25
Huang, Xiaojie; Stodieck, Sophia K; Goetze, Bianka et al. (2015) Progressive maturation of silent synapses governs the duration of a critical period. Proc Natl Acad Sci U S A 112:E3131-40

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