Cocaine addiction is a serious public health problem. There are no FDA approved medications for the treatment of cocaine addiction. Previous studies have shown that phosphodiesterase-4 (PDE-4) inhibitor rolipram reduces addictive behavior by multiple drugs of abuse in multiple behavior assays and the ventral tegmental area (VTA) is a primary site that mediates its action. Considering that PDE4 and non-selective PDE inhibitors ameliorate aging-related metabolic phenotypes in animal studies and show effectiveness in treating respiratory diseases and depression in clinical trials, these inhibitors are a promising candidate for developing anti-addiction medications with potential health benefits. The goal of this project is to investigate neural circuits and downstream signaling mechanisms that mediate PDE inhibitor-induced attenuation of cocaine conditioned place preference (CPP) and locomotor sensitization. The central hypothesis is that the PDE inhibitors reduce the behavioral effects of cocaine through activation of exchange proteins activated by cAMP (Epac) and inhibition of the mammalian target of rapamycin (mTOR) signaling in the VTA. The hypothesis will be tested through three Specific Aims: 1) Test if the PDE inhibitors activate Epac signaling in VTA dopamine neurons to attenuate cocaine-induced CPP and locomotor sensitization. Under this Aim, we will use the designer receptors exclusively activated by designer drugs (DREADD) technology to interrogate the neuronal cell-type that mediates the action of PDE inhibitors. We will examine whether disruption of Epac signaling in the VTA abrogates the behavioral effects of the PDE inhibitors. 2) Investigate synaptic mechanisms by which the PDE inhibitors attenuate cocaine CPP. Under this Aim, we will test the hypothesis that the PDE inhibitors induce long-term depression-like synaptic modification, which """"""""neutralizes"""""""" cocaine-evoked synaptic potentiation and provides a potential mechanism for the reduction in cocaine CPP induced by PDE inhibitors. 3) Test whether PDE inhibitors reduce cocaine CPP and locomotor sensitization through inhibition of mTOR signaling. Under this Aim, we will use a cre-loxP system to produce conditional knockout of mTOR in the VTA and examine its impact on cocaine-induced CPP and behavioral sensitization and behavioral changes induced by the PDE inhibitors. The identification of downstream targets and molecular mechanisms that mediate the action of the PDE inhibitors is a critical first step toward """"""""repurposing"""""""" PDE inhibitors for anti-addiction medications.
The proposed research is relevant to public health because the discovery of the molecular targets and mechanisms by which phosphodiesterase (PDE) inhibitors reduce cocaine-induced addictive behavior will contribute knowledge at both mechanistic and practical levels for the development and testing of therapeutic strategies for the treatment of cocaine addiction.
|Lee, Sang H; Shin, Seung Min; Zhong, Peng et al. (2018) Reciprocal control of excitatory synapse numbers by Wnt and Wnt inhibitor PRR7 secreted on exosomes. Nat Commun 9:3434|
|Liu, Xiaojie; Li, Yan; Yu, Laikang et al. (2018) VTA mTOR Signaling Regulates Dopamine Dynamics, Cocaine-Induced Synaptic Alterations, and Reward. Neuropsychopharmacology 43:1066-1077|
|Zhong, Peng; Vickstrom, Casey R; Liu, Xiaojie et al. (2018) HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress. Elife 7:|
|Tong, Jiaqing; Liu, Xiaojie; Vickstrom, Casey et al. (2017) The Epac-Phospholipase C? Pathway Regulates Endocannabinoid Signaling and Cocaine-Induced Disinhibition of Ventral Tegmental Area Dopamine Neurons. J Neurosci 37:3030-3044|
|Liu, Xiaojie; Zhong, Peng; Vickstrom, Casey et al. (2017) PDE4 Inhibition Restores the Balance Between Excitation and Inhibition in VTA Dopamine Neurons Disrupted by Repeated In Vivo Cocaine Exposure. Neuropsychopharmacology 42:1991-1999|
|McReynolds, Jayme R; Doncheck, Elizabeth M; Li, Yan et al. (2017) Stress Promotes Drug Seeking Through Glucocorticoid-Dependent Endocannabinoid Mobilization in the Prelimbic Cortex. Biol Psychiatry :|
|Lu, Hui; Liu, Qing-Song (2017) Serotonin in the Frontal Cortex: A Potential Therapeutic Target for Neurological Disorders. Biochem Pharmacol (Los Angel) 6:|
|Liu, Xiaojie; Chen, Yao; Tong, Jiaqing et al. (2016) Epac Signaling Is Required for Cocaine-Induced Change in AMPA Receptor Subunit Composition in the Ventral Tegmental Area. J Neurosci 36:4802-15|
|Liu, Qing-Song (2016) Medical Marijuana-Opportunities and Challenges. Biochem Pharmacol (Los Angel) 5:|
|Ogasawara, Daisuke; Deng, Hui; Viader, Andreu et al. (2016) Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition. Proc Natl Acad Sci U S A 113:26-33|
Showing the most recent 10 out of 21 publications