Cocaine addiction remains a critical medical and social problem. A prominent guiding hypothesis for the molecular and cellular research of drug addiction is the neuroadaptation theory, which suggests that addictive drugs usurp common neural plasticity mechanisms that normally help form episodic memories to instead form addiction-related memories. Although this theory has been supported by the striking similarities between drug-induced cellular adaptations and experience-dependent neural plasticity, it falls short in explaining how addiction-related memories are extremely durable and resistant to extinction. Using cocaine as the drug model, we have begun to address this critical point over the past few years by hypothesizing that exposure to cocaine wakes up dormant, highly-efficient cellular mechanisms that are otherwise only present in the developing brain to profoundly reform specific neural circuits, resulting in extremely durable circuitry and behavioral alterations associated with addiction. This hypothesis was based on our initial observation (published in 2009) that exposure to cocaine generates a large number of silent excitatory synapses in the nucleus accumbens shell (NAc), an essential brain region for motivated behaviors. Silent synapses usually only contain NMDA receptors (NMDARs), with AMPA receptors (AMPARs) either absent or highly labile. Thus, these synapses are often silent at near resting membrane potentials. Abundant in the developing brain, many silent synapses are thought to be immature synaptic contacts; upon maturation by recruiting/stabilizing AMPARs, silent synapses may evolve into fully functional synapses to form new circuits. As such, the generation and potential maturation of silent synapses may be one of the critical developmental mechanisms that exposure to cocaine resumes to induce long-lasting circuitry and behavioral alterations. Among extensive excitatory synaptic inputs to the NAc, the afferents from the medial prefrontal cortex (mPFC) are particularly important for several core aspects of cocaine addiction including cocaine seeking and craving after withdrawal from cocaine self-administration (SA). Our current preliminary results show that silent synapses are generated within the mPFC-to-NAc pathway, and maturation of cocaine-generated silent synapses within this pathway is temporally correlated with the progressive intensification of cocaine seeking (incubation of cocaine craving). Using cocaine SA and seeking as the animal models, we will test the hypothesis that cocaine SA recruits developmental mechanisms to generate silent synapses within the mPFC-to-NAc pathway in the adult rat brain; maturation of these synapses during cocaine withdrawal and the resulting re-organization of the mPFC-to-NAc pathway critically contribute to withdrawal-associated cocaine craving and seeking. Expected outcomes of the proposed research will unveil novel molecular and cellular processes contributing to cocaine relapse and provide molecular targets for potential clinical treatment.
Cocaine addiction remains an urgent and unmet medical need. The proposed work attempts to characterize cocaine-induced circuitry re-organization in the prefrontal cortex to nucleus accumbens pathway. The expected outcomes will define a novel mechanism for cocaine seeking and cocaine craving during withdrawal from cocaine self-administration.
| Logan, Ryan W; Hasler, Brant P; Forbes, Erika E et al. (2018) Impact of Sleep and Circadian Rhythms on Addiction Vulnerability in Adolescents. Biol Psychiatry 83:987-996 |
| Parekh, Puja K; Becker-Krail, Darius; Sundaravelu, Poornima et al. (2018) Altered GluA1 (Gria1) Function and Accumbal Synaptic Plasticity in the Clock?19 Model of Bipolar Mania. Biol Psychiatry 84:817-826 |
| Parekh, Puja K; Sidor, Michelle M; Gillman, Andrea et al. (2018) Antimanic Efficacy of a Novel Kv3 Potassium Channel Modulator. Neuropsychopharmacology 43:435-444 |
| Wang, Junshi; Ishikawa, Masago; Yang, Yue et al. (2018) Cascades of Homeostatic Dysregulation Promote Incubation of Cocaine Craving. J Neurosci 38:4316-4328 |
| Yu, Jun; Yan, Yijin; Li, King-Lun et al. (2017) Nucleus accumbens feedforward inhibition circuit promotes cocaine self-administration. Proc Natl Acad Sci U S A 114:E8750-E8759 |
| 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 |
| 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, Yanhua H; Schlüter, Oliver M; Dong, Yan (2015) Silent Synapses Speak Up: Updates of the Neural Rejuvenation Hypothesis of Drug Addiction. Neuroscientist 21:451-9 |
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