Glutamate is a major neurotransmitter in the brain, and its role in drug addiction remains a hot topic in animal research aimed to unravel neurochemical mechanisms for addictive properties of drugs of abuse. This lab has long been supported for studying roles of metabotropic glutamate receptors (mGluRs). In the last period of grant, we have identified that group I mGluRs (mGluR1 and 5 subtypes) that are densely expressed in the striatum are key regulators of drug action. Specifically, activation of group I mGluRs is required for acutely- administered psychostimulant amphetamine (AMPH) to enhance endogenous dynorphin activity in rat striatal neurons, a critical response that was thought to homeostatically inhibit drug effects. One form of long-lasting behavioral plasticity, behavioral sensitization to repeated AMPH injections in rats, is a widely-used animal model because it mimics the intensification of drug craving in human addicts. Interestingly, we have recently found that repeated AMPH administration markedly reduced group I mGluR mRNAs and proteins in the striatum. This raises an innovative question as to whether repeated AMPH injections could progressively downregulate the group I mGluR expression and thus function in activating inhibitory dynorphin and thereby induce behavioral sensitization. In this continuation proposal, a series of experiments was therefore proposed to evaluate an overarching hypothesis that the downregulation of group I mGluRs contributes to behavioral sensitization to repeated AMPH administration. Using multidisciplinary approaches, this hypothesis will be tested in rodents in vivo in three AIMs. In these AIMs, we will (1) explore and characterize the reduction of mGluR1 and mGluR5 protein expression in the striatum in response to repeated AMPH administration, and elucidate cellular mechanisms for such reduction, (2) define functional consequences of reduced mGluR1/5 expression in terms of mGluR1/5-mediated functions by examining effects of repeated AMPH administration on the prime mGluR1/5-mediated cellular and genomic responses in striatal neurons, including phosphoinositide hydrolysis, intracellular Ca2+ release, MAPK/ERK activation, transcription factor (CREB) phosphorylation, and dynorphin gene expression, and (3) define functional roles of the downregulated mGluR1/5 in behavioral sensitization by examining behavioral sensitization to repeated AMPH administration in rats in which reduced mGluR1/5 protein expression is reversed or restored by viral-mediated transgene expression or by proteasome inhibitors, or in rats in which mGluR1/5 proteins are experimentally reduced by an antisense or genetic approach. Results achieved here from molecule to behavior will provide evidence for a new molecular mechanism underlying drug action, and will ultimately contribute to the development of novel pharmacotherapies, by targeting the group I mGluRs, for the treatment of various mental illnesses stemmed from substance abuse.

Public Health Relevance

Substance abuse and addiction is among major social, economic, and health problems. This application is proposed to discover brain mechanisms critical for the addictive properties of drugs of abuse. The findings through this research project will promote the development of novel pharmacotherapies for the treatment of various mental illnesses stemmed from substance abuse.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Wu, Da-Yu
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Missouri Kansas City
Other Basic Sciences
Schools of Medicine
Kansas City
United States
Zip Code
Mao, Li-Min; Jin, Dao-Zhong; Xue, Bing et al. (2014) Phosphorylation and regulation of glutamate receptors by CaMKII. Sheng Li Xue Bao 66:365-72
Wang, John Q; Guo, Ming-Lei; Jin, Dao-Zhong et al. (2014) Roles of subunit phosphorylation in regulating glutamate receptor function. Eur J Pharmacol 728:183-7
Xue, Bing; Edwards, Matthew C; Mao, Li-Min et al. (2014) Rapid and sustained GluA1 S845 phosphorylation in synaptic and extrasynaptic locations in the rat forebrain following amphetamine administration. Neurochem Int 64:48-54
Song, Lu; Yang, Xinxin; Ma, Yaping et al. (2014) The CB1 cannabinoid receptor agonist reduces L-DOPA-induced motor fluctuation and ERK1/2 phosphorylation in 6-OHDA-lesioned rats. Drug Des Devel Ther 8:2173-9
Mao, Li-Min; Hastings, James M; Fibuch, Eugene E et al. (2014) Propofol selectively alters GluA1 AMPA receptor phosphorylation in the hippocampus but not prefrontal cortex in young and aged mice. Eur J Pharmacol 738:237-44
Mao, Li-Min; Diaz, Jesus A; Fibuch, Eugene E et al. (2013) Regulation of phosphorylation of synaptic and extrasynaptic GluA1 AMPA receptors in the rat forebrain by amphetamine. Eur J Pharmacol 715:164-71
Mao, Li-Min; Reusch, James M; Fibuch, Eugene E et al. (2013) Amphetamine increases phosphorylation of MAPK/ERK at synaptic sites in the rat striatum and medial prefrontal cortex. Brain Res 1494:101-8
Guo, Ming-Lei; Xue, Bing; Jin, Dao-Zhong et al. (2013) Dynamic downregulation of Nogo receptor expression in the rat forebrain by amphetamine. Neurochem Int 63:195-200
Jin, Dao-Zhong; Guo, Ming-Lei; Xue, Bing et al. (2013) Differential regulation of CaMKII? interactions with mGluR5 and NMDA receptors by Ca(2+) in neurons. J Neurochem 127:620-31
Carino, Charlene; Fibuch, Eugene E; Mao, Li-Min et al. (2012) Dynamic loss of surface-expressed AMPA receptors in mouse cortical and striatal neurons during anesthesia. J Neurosci Res 90:315-23

Showing the most recent 10 out of 41 publications