Molecular Neuropharmacology Laboratory
Director: Jiang-Fan Chen, MD, PhD
Adenosine, a naturally occurring nucleoside, exists ubiquitously throughout the body as a cellular metabolic intermediary and also functions as a neuromodulator in brain. Extracellular levels of adenosine increase drastically in response to stress insults that compromise the ATP energy metabolism. The biological functions of extracellular adenosine are mediated through four G-protein coupled receptor adenosine subtypes: A1, A2A, A2B and A3. The brain A2A adenosine receptor is particularly attracted because it co-expresses with D2 dopamine receptors in the striatum, and can profoundly modulate the activities of dopaminergic and other neurotransmitter systems. Our research focuses on the neurobiology of the A2A adenosine receptor, with particular emphasis on the role it may play in the development and treatment of neuropsychiatric disorders ranging from Parkinson’s disease to drug addiction.
To systematically approach adenosine receptor function in vivo, we (together with Drs. Michael A. Schwarzschild and J. Stephen Fink then at Massachusetts General Hospital) have developed an A2A receptor knockout mouse model. Currently, we are employing various genetic knockout models (including A2A KO, D2 KO and A2A-D2 double KO) coupled with pharmacological manipulation to explore the pathophysiological role of A2A receptors in a variety of animal and cellular models of neuropsychiatric disorders. We are studying the A2A receptor functions at behavioral (locomotor activity), neurochemical (dopamine and glutamate neurotransmission), and cellular (molecular markers and potential mediators) levels to gain insights into the integrated neural function of adenosine receptors in vivo. Our immediate research goals are (1) to define the molecular and cellular mechanisms underlying the profound adenosine-dopamine interactions in brain; (2) to investigate novel neuroprotective effects of adenosine receptors in response to neural insults in several animal models of neurological disorders; (3) to explore potential therapeutic benefits of A2A receptor antagonists for Parkinson’s disease: enhancement of motor function, prevention of L-dopa-induced dyskinesia, and attenuation of dopaminergic neuron degeneration. The knowledge derived from these studies may provide the neurobiological basis for rational development of A2A receptor agents as novel treatment strategies for neuropsychological disorders, ranging from Parkinson’s disease to drug addiction. Our long-term goal is to understand the physiological function of adenosine as a homeostatic mechanism, and the pathophysiological role of adenosine as a cellular defense mechanism in response to stress insults.
(1) Chen J-F, Huang Z-H, Ma J, Zhu J-M, Moratalla R, Standaert DG, Moskowitz MA, Fink JS. Schwarzschild MA (1999) A2A adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice. Journal of Neuroscience. 19:9192-9200
(2) Chen J-F, Moratalla R, Impagnatiello F, Grandy DK, Cuellar B, Rubinstein M, Beilstein MA, Hackett E, Fink JS, Low MJ, Ongini E, Schwarzschild MA (2001) The role of D2 dopamine receptors in A2A adenosine receptor-induced behavioral and cellular responses as revealed by A2A and D2 receptor knockout mice. Proceeding of National Academy of Science, USA 98:1970-1975.
(3) Chen J-F, Xu K, Jacques Petz J, Staal R, Xu Y-H, Sonsalla P.K., Castagnoli K, Neal Castagnoli, N and Michael A. Schwarzschild (2001) Caffeine and A2A adenosine receptor inactivation attenuate dopaminergic toxicity in the MPTP model of Parkinson’s disease. Journal of Neuroscience. 21: RC143 (1-6).
(4) Fredduzzi S, Moratalla R, Monopoli A, Cuellar B, Xu K, Ongini E, Impagnatiello F, Schwarzschild MA and Chen J-F. (2002) Persistent behavioral sensitization to chronic L-dopa requires A2A adenosine receptors. Journal of Neuroscience 22:1054-1062.
(5) Chen J-F, Steyn S, Staal R, Petzer J, Xu K, Castagnoli K, Sonsalla PK, Castagnoli N, Jr. and Schwarzschild MA (2002) 8-(3-chlorostyryl) caffeine may attenuate MPTP neurotoxicity through dual actions of MAO Inhibition and A2A receptor antagonism. Journal of Biological Chemistry. 277:36040-36044.