Our long-term research interest is to understand the molecular basis of neuronal function under both normal and diseased conditions with an emphasis on drug addiction. Drug addiction is a brain disease and it impacts about 15% of the population. This disease is one of the foremost public health problems in the U.S. and in the world. It is characterized by the compulsive seeking and taking of a drug despite known adverse consequences. Once acquired, it is long-lasting and difficult to extinguish. Memories of drug experience and drug-associated environmental cues can elicit drug seeking and taking behaviors. Relapse to drug-taking is the main obstacle to long-term treatment and cure for drug addiction in humans. Currently, there are few strategies for treating drug addiction. The development of effective treatment of drug addiction relies on a thorough understanding of the neurobiological mechanisms underlying the compulsiveness and persistence of drug-induced behaviors as well as susceptibility to relapse. An emerging theme in drug addiction research is that dopamine is a brain neurotransmitter that functions in reward learning through its receptors, and drugs of abuse can pathologically change reward-related learning circuits in the brain’s dopamine system. We have been investigating the key dopamine receptors and related intracellular mediators that are involved in reward-related learning induced by drugs of abuse. Combining behavioral, genetic, anatomical and molecular biological methods, we have found that several protein molecules, including dopamine D1 and D3 receptors as well as the transcription c-Fos are involved in mediating the various effects of drugs of abuse including cocaine. We are further investigating the molecular basis involved in the reconsolidation, extinction and reinstatement of cocaine-induced reward learning. Our ultimate goal is to use our findings to improve treatment for individuals with substance abuse disorders.
Zhang, J., Zhang, L., Jiao, H., Zhang, Q., Zhang, D., Lou, D., Katz, J., and Xu, M. (2006). c-fos facilitates acquisition and extinction of cocaine-induced persistent change. J. Neurosci. 26: 13287-13296.
Jiao, H., Zhang, L., Gao, F., Lou, D., Zhang, J. and Xu, M. (2007). Dopamine D1 and D3 receptors oppositely regulate NMDA- and cocaine-induced MAPK signaling via NMDA receptor phosphorylation. J. Neurochem. 103: 840-848.
Caine, S.B., Thomsen, M., Gabriel, K.I., Berkowitz, J.S., Gold, L.H., Koob, G.F., Tonegawa, S., Zhang, J. and Xu, M. (2007). Decreased cocaine self-administration in dopamine D-1 receptor knockout mice. J. Neurosci. 27: 13140-13150.
Hu, X.T., Nasif, F.J., Zhang, J. and Xu, M. (2008). Fos regulates neuronal activity in the nucleus accumbens. Neurosci. Letters 448: 157–160.
Liu, X., Mao, L., Zhang, G., Papasian, C.J., Fibuch, E.E., Lan, H., Zhou, H., Xu, M.* and Wang, J.Q.* (2009). Activity-dependent modulation of limbic dopamine D3 receptors by CaMKII. Neuron 61: 425-438. *Co-correspondence.
Note: Work described in the Liu et al. paper received a special commentary. See Hell, J.W. (2009). Hooked on the D3 Receptor: CaMKII’s new addiction. Neuron 61: 335-336.
Campioni, M., Xu, M. and McGehee, D.S. (2009). Stress-induced changes in nucleus accumbens glutamate synaptic plasticity. J. Neurophys. 101: 3192-3198.
Zhou, F-W., Jin, Y., Matta, S., Xu, M. and Zhou, F-M. (2009). An ultra-short dopamine pathway regulates basal ganglia output. J. Neurosci. 29: 10424-10435.
Fan, X., Xu, M. and Hess, E.J. (2010). D2 dopamine receptor subtype-mediated hyperactivity and amphetamine responses in a model of ADHD. Neurobio. Dis. 37: 228-236.
Ren, Z., Sun, W., Jiao, H., Zhang, D., Kong, H., Wang, X. and Xu, M. (2010). Dopamine D1 and NMDA receptors and ERK mediate neuronal morphological changes induced by repeated cocaine administration. Neurosci. 168: 48-60.
Chen, L.P. and Xu, M. (2010). Dopamine D1 and D3 receptors are differentially involved in cue-elicited cocaine seeking. J. Neurochem. 114: 530-541.
Xing, B., Kong, H., Meng, X., Wei, S., Xu, M. and Li, S. (2010). Dopamine D1 but not D3 receptor is critical for spatial memory and related signaling in the hippocampus. Neurosci. 169: 1511-1519.
Kong, H., Kuang, W., Li, S. and Xu, M. (2011). Activation of dopamine D3 receptors inhibits reward-related learning induced by cocaine. Neurosci. 176: 152–161.
Kong, H. and Xu, M. (2011). Exploring mechanisms underlying extinction of cue-elicited cocaine seeking. Current Neuropharm. 9: 8-11.
