David A. Baker, Ph.D.

Associate Professor

Associate Chair

B.S., 1992, Montana State University

Ph.D., 1999, Arizona State University

Postdoctoral Fellow, Medical University of South Carolina

Schroeder Health Complex, 405

(414) 288-6638 or 288-6635

E-mail

Probing Outside of the Synapse: Contribution of Extrasynaptic Glutamate to Neuropsychiatric Disorders

Glutamate represents the primary excitatory neurotransmitter and is involved in most aspects of brain functioning in the normal and diseased states.  While synaptically released glutamate has been studied in great detail, a dearth of knowledge exists regarding the contribution of extrasynaptic glutamate release mechanisms, including cystine-glutamate antiporters (also referred to as system xc-), to pathological conditions involving glutamate dysfunction.  The focus of my research is to determine whether extrasynaptic release mechanisms represent unrecognized targets in unmasking the etiology and treatment of psychiatric disorders, namely schizophrenia and cocaine addiction.

We utilize a pathophysiological approach whereby the involvement of extrasynaptic release mechanisms in neuropsychiatric disorders is examined using preclinical models of schizophrenia and cocaine addiction.  Towards this end, the laboratory incorporates a number of molecular, neurochemical, and behavioral techniques to address these questions.  Funding for these endeavors is provided by grants from the National Institute on Drug Abuse, National Institute of Mental Health, the Biomedical Technology Alliance, and the National Alliance for Research on Schizophrenia and Depression awarded to DAB.

The People
Ilangovan Raju	PhD's	Kristen Kau
Victoria Lutgen	Ph.D. Students	Aric Madayag

Sample Projects Recently Completed:

Contribution of Cystine-Glutamate Antiporters to the Phencyclidine Model of Schizophrenia.  In this project, we examined whether activation of cystine-glutamate antiporters using the cysteine prodrug N-acetylcysteine would blunt abnormal behaviors used to model schizophrenia.  First, we demonstrate that N-acetylcysteine treatment can modulate glutamate levels in the prefrontal cortex, which is thought to contribute to symptoms of schizophrenia that respond poorly to current antipsychotic agents.  Next, we found that N-acetylcysteine improves working-memory deficits and social interaction, examples of symptoms that are difficult to treat with current medications.  Interestingly, assessment of protein levels in post mortem tissue obtained from schizophrenic patients revealed significant changes in xCT, the active subunit for cystine-glutamate exchange, in the dorsolateral prefrontal cortex.  These data illustrate that nonvesicular glutamate release mechanisms may contribute to the pathology underlying schizophrenia and represent novel targets in the treatment of the disease.

Drug-Induced Plasticity Contributing to Heightened Relapse Susceptibility: Neurochemical Changes & Augmented Reinstatement in High-Intake Subjects.  In this project, we examined whether drug-induced adaptations that are necessary to generate cocaine-induced reinstatement also determine relapse vulnerability.  To do this, we compared neurochemical changes between low- and high-drug intake subjects.  In particular, we were interested in learning whether subjects that consume high levels of cocaine display augmented levels of the neurotransmitter glutamate or dopamine, both of which have been shown to be important for relapse behaviors.  Contrary to our expectation, cocaine-induced dopamine, but not glutamate, was higher in high-intake subjects.  Augmented cocaine-induced dopamine may be due, in part, to blunted cystine-glutamate exchange by system xc- since the cysteine prodrug N-acetylcysteine blocked this effect.  Thus, this further implicates dopamine in relapse vulnerability, and may indicate a novel mechanism whereby N-acetylcysteine produces anti-craving effects (see next project).

Repeated Administration of N-acetylcysteine on Cocaine-induced Drug Seeking and Craving. In collaboration with investigators at the Medical College of Wisconsin, we have found that the subchronic N-acetylcysteine treatment reduces cocaine seeking and craving produced by exposure to a cocaine-paired cue or a cocaine injection to non-treatment seeking human drug abusers.  These data further support the conclusion that glutamate release from system xc- represents a novel target in the treatment of addiction.

Sample Projects Recently Initiated:

The near-term research goals include determining how:

• cocaine reduces cystine-glutamate exchange
• diminished cystine-glutamate exchange contributes to plasticity relevant to cocaine addiction and schizophrenia
• cystine-glutamate exchange is regulated in the normal and diseased brain (e.g., addiction and schizophrenia)

Toward the first and third points, we will continue studies initiated last year that examine the regulation of cystine-glutamate exchange by other neurotransmitter systems.  We have collected data demonstrating the regulation of cystine-glutamate exchange by D1 receptor stimulation, and changes in PKA activity.  We are in the process of identifying the phosphorylation site of xCT using single-point mutations of likely sites.  Toward the second point, we will continue examining the impact of infusion of adeno-associated viruses containing xCT cDNA or siRNA on cocaine-primed reinstatement and glutamate signaling in the nucleus accumbens. 

Publications:

1. Kau, K., Madayag, A., Mantsch, J.R., Grier, M.D., Abdulhameed, O., Baker, D.A. (2008) Blunted System xc- in the Nucleus Accumbens Promotes Cocaine-Induced Drug Seeking. Neuroscience, 155, 530-557
2. Baker, D.A., Madayag, A., Meador-Woodruff, J.H., Kristiansen, L., Haroutunian, V., and Raju I. (2008) Contribution of cystine-glutamate antiporter to the psychotomimetic effects of phencyclidine, Neuropsychopharmacology, 33, 1760-1772
3. Mantsch, J.R., Baker, D.A., Francis, D.M., Katz, E.S., Hoks, M.A., Serge, J.P (2008) Stressor- and corticotropin releasing factor-induced reinstatement and active stress-related behavioral responses are augmented following long-access cocaine self-administration. Psychopharmacology, 195, 591-603
4. Mantsch, J.R., Baker, D.A., Serge, J.P., Hoks, M.A., Francis, D.M., Katz, E.S. (2008) Surgical adrenalectomy with diurnal corticosterone replacement slows escalation and prevents the augmentation of cocaine-induced reinstatement in subjects self-administering cocaine under long-access conditions. Neuropsychopharmacology, 33, 814-26
5. Madayag, A., Lobner, D., Kau, K., Mantsch, J., Abdulhameed, O., Hearing, M., Grier, M., Baker, D.A. (2007) Repeated N-Acetylcysteine Administration Alters Plasticity-Dependent Effects of Cocaine.  Journal of Neuroscience 27, 13968-13976
6. Mantsch, J.R., Cullinan, W.E., Tang, L.C., Baker, D.A., Katz, E.S., Hoks, M.A., Ziegler, D.R. (2007) Daily cocaine self-administration under long-access conditions augments restraint-induced increases in plasma corticosterone and impairs glucocorticoid receptor-mediated negative feedback. Brain Research, 1167, 101-111
7. Mantsch, J.R., Li, S.J., Risinger, R., Awad, S., Katz, E., Baker, D.A., Yang, Z (2007) Levo-tetrahydropalmatine attenuates cocaine self-administration and cocaine-induced reinstatement. Psychopharmacology, 192, 581-91
8. Baker, D.A. and Kalivas P.W. (2006) The significance of glutamate in microdialysates. Handbook of Microdialysis, Eds: B.H.C. Westerink & T.I.F.H. Cremers, Elsevier
9. Baker, D.A. and Kalivas, P.W. (2005) Sensitization and Relapse:  Dopamine-Glutamate Interactions: In: Dopamine and glutamate in psychiatric disorders.  Ed: W.J. Schmidt, Humana Press
10. Baker, D.A., McFarland, K., Lake, R.W., Shen, H., Toda, S., Kalivas, P.W. (2003) Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse.  Nature Neuroscience, 6, 743-749
11. Kalivas, P.W., Toda, S., Bowers M.S., Baker, D.A., Ghasemzadeh, M.B. (2003) The temporal sequence of changes in gene expression by drugs of abuse.  Methods Mol. Med. 79, 3-11
12. Xi, Z.X., Shen, H., Baker, D.A., & Kalivas, P.W. (2003) Inhibition of non-vesicular glutamate release by group III metabotropic glutamate receptors in the nucleus accumbens.  J Neurochemistry, 87, 1204-12
13. Baker, D.A., Xi, Z.X., Shen H., Swanson C.J., & Kalivas, P.W. (2002) The primary source and neuronal function of in vivo non-synaptic glutamate.  Journal of Neuroscience, 22, 9134-9141
14. Baker, D.A., Shen, H., and Kalivas, P.W. (2002) Cystine-glutamate exchange serves as the source for extracellular glutamate:  Modifications by repeated cocaine administration.  Amino Acids, 23, 161-162
15. Xi, Z.X., Ramamoorthy, S., Baker, D.A., Shen, H., Samuvel, D.J., Kalivas, P.W. (2002) Modulation of group II metabotropic glutamate receptor signaling by chronic cocaine.  Journal of Pharmacology and Experimental Therapeutics, 303, 608-615
16. Xi, Z.X., Baker, D.A., Shen, H., Carson, D.S. & Kalivas, P.W. (2002) Group II metabotropic glutamate receptors modulate extracellular glutamate in the nucleus accumbens.  Journal of Pharmacology and Experimental Therapeutics, 300, 1-10
17. Baker, D.A. and Kalivas, P.W. (2002) Glutamate and Dopamine Interactions in the Motive Circuit: In: Implications for Craving. Glutamate and Addiction, Eds: B.H. Herman, J. Frankenheim, R. Litten, P. Sheridan, F.F. Weight, & S.R. Zukin, Humana Press
18. Swanson, C.J., Baker, D.A., Carson, D., Worley, P.F., Kalivas, P.W. (2001) Repeated cocaine administration attenuates group I metabotropic glutamate receptor-mediated glutamate release and behavioral activation: A potential role for Homer1bc.  Journal of Neuroscience, 21, 9043-9052
19. Baker, D.A., Tran-Nguyen, L.T.L., Fuchs, R.A., and Neisewander, J.L. (2001) Differential effects of chronic fluoxetine treatment on cocaine-seeking behavior elicited by cocaine or a cocaine environment.  Psychopharmacology, 155, 18-26
20. Neisewander, J.L., Baker, D.A., Fuchs, R.A., Tran-Nguyen, L.T.L., Palmer, A., Marshall, J.F. (2000) Fos protein expression and cocaine-seeking behavior after exposure to a cocaine self-administration environment.  Journal of Neuroscience, 20, 798-805
21. Tran-Nguyen, L.T.L., Baker, D.A., Grote, K.A., Solano, J., and Neisewander, J.L (1999) Serotonin depletion attenuates cocaine-, but not food-seeking behavior.  Psychopharmacology, 146, 60-66
22. DeMarse, T.B., Killeen, P.R., and Baker, D.A. (1999) Satiation causes decreases in within-session responding.  Journal of the Experimental Analysis of Behavior, 72, 407-423
23. Tran-Nguyen, L.T.L., Fuchs, R.A., Coffey, G.E., Baker, D.A., O’Dell, L.E., and Neisewander, J.L. (1998) Time-dependent changes in cocaine-seeking behavior and dopamine overflow in the amygdala during cocaine withdrawal.  Neuropsychopharmacology, 19, 48-59
24. Baker, D.A., Fuchs, R.A., Specio, S.E., Khroyan, T.V., and Neisewander, J.L. (1998) Effects of SCH-23390 on cocaine-induced locomotion and conditioned place preference.  Synapse, 30, 181-193
25. Baker, D. A., Specio, S. E., Tran-Nguyen, T. L., & Neisewander, J. L. (1998) Amphetamine infusions into the ventrolateral striatum produce conditioned place preference.  Pharmacology, Biochemistry, and Behavior, 61, 107-111
26. Khroyan, T.V., Baker, D.A., Fuchs, R.A., and Neisewander, J.L (1998) Differential effects of 7-OH-DPAT on amphetamine-induced behaviors and conditioned place preference.  Psychopharmacology, 139, 332-341
27. Khroyan, T.V., Fuchs, R.A., Baker, D.A., and Neisewander, J.L. (1997) Effects of the dopamine D-3 preferring agonists 7-OH-PIPAT and PD-128,907 on motor behaviors and place conditioning.  Behavioral Pharmacology, 8, 1-10
28. Baker, D.A., Khroyan, T.V., O'Dell, L.E., Fuchs, R.A., and Neisewander, J.L. (1996) Differential effects of intra-accumbens sulpiride on cocaine-induced locomotion and conditioned place preference.  Journal of Pharmacology and Experimental Therapeutics, 279, 392-404
29. Khroyan, T.V., Baker, D.A., and Neisewander, J.L. (1995) Effects of the dopamine D-3 preferring agonist 7-OH-DPAT on behaviors and place conditioning.  Psychopharmacology, 122, 351-357
30. Babcock, A.M., Baker, D.A., Hallock, N.L., Lovec, R., Lynch, W.C., and Peccia, J.C. (1993) Neurotensin-induced hypothermia prevents hippocampal neuronal damage and increased locomotor activity in ischemia.  Brain Research Bulletin, 32, 373-378
31. Babcock, A.M., Baker, D.A., and Lovec, R. (1993) Locomotor activity in the ischemic subject.  Brain Research, 625, 351-354
32. Babcock, A.M., Baker, D.A., and Moody, T.W. (1992) Bombesin-induced hypothermia and receptor antagonist study.  Pharmacology, Biochemistry, and Behavior, 43, 957-960