A plethora of evidence has implicated the improper functioning of the prefrontal cortex in the pathophysiology of schizophrenia. While numerous findings have described a role for monoaminergic and cholinergic projections to the prefrontal cortex in the cognitive functions associated with this region, the extent of the involvement of the most prevalent prefrontal cortex afferents, namely those projections that contain glutamate as their neurotransmitter, in mnemonic, attentional, and other associative functions of the prefrontal cortex has not been well characterized. Considering that a number of recent findings are suggestive of glutamatergic abnormalities in schizophrenia, it is imperative that more be learned about the role of glutamate receptors in cognitive functions that are relevant to schizophrenic symptomatology. The research proposed in this request for an Independent Scientist Award (K02) involves characterizing the contribution of glutamate receptors in regulating those associative functions of the prefrontal cortex that are relevant to the pathophysiology of schizophrenia. This award will allow the applicant to devote maximal effort to the above research objectives which entails receiving appropriate training in order to establish in her laboratory behavioral paradigms that have direct relevance to different aspects of the cognitive dysfunctions associated with schizophrenia and that are analogous to clinical tests at which patients with schizophrenia show an impairment. Considering that the present mode of therapy for schizophrenia, i.e., treatment with antidopaminergic drugs, does not effectively treat cognitive deficits associated with this disorder, an understanding of the neurochemical basis of associative functions of the prefrontal cortex will help in the development of novel pharmacotherapeutic strategies for the treatment of schizophrenia.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Scientist Development Award - Research (K02)
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Special Emphasis Panel (ZRG1-BDCN-6 (01))
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Winsky, Lois M
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Yale University
Schools of Medicine
New Haven
United States
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Homayoun, Houman; Moghaddam, Bita (2009) Differential representation of Pavlovian-instrumental transfer by prefrontal cortex subregions and striatum. Eur J Neurosci 29:1461-76
Stefani, Mark Renato; Moghaddam, Bita (2005) Transient N-methyl-D-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia. Biol Psychiatry 57:433-6
Homayoun, Houman; Jackson, Mark E; Moghaddam, Bita (2005) Activation of metabotropic glutamate 2/3 receptors reverses the effects of NMDA receptor hypofunction on prefrontal cortex unit activity in awake rats. J Neurophysiol 93:1989-2001
Jackson, Mark E; Moghaddam, Bita (2004) Stimulus-specific plasticity of prefrontal cortex dopamine neurotransmission. J Neurochem 88:1327-34
Homayoun, Houman; Stefani, Mark R; Adams, Barbara W et al. (2004) Functional Interaction Between NMDA and mGlu5 Receptors: Effects on Working Memory, Instrumental Learning, Motor Behaviors, and Dopamine Release. Neuropsychopharmacology 29:1259-69
Stefani, Mark R; Groth, Karyn; Moghaddam, Bita (2003) Glutamate receptors in the rat medial prefrontal cortex regulate set-shifting ability. Behav Neurosci 117:728-37
Takahata, Ryuichi; Moghaddam, Bita (2003) Activation of glutamate neurotransmission in the prefrontal cortex sustains the motoric and dopaminergic effects of phencyclidine. Neuropsychopharmacology 28:1117-24
Lipska, Barbara K; Aultman, Julie M; Verma, Anita et al. (2002) Neonatal damage of the ventral hippocampus impairs working memory in the rat. Neuropsychopharmacology 27:47-54
Moghaddam, Bita (2002) Stress activation of glutamate neurotransmission in the prefrontal cortex: implications for dopamine-associated psychiatric disorders. Biol Psychiatry 51:775-87
Adams, Barbara W; Bradberry, Charles W; Moghaddam, Bita (2002) NMDA antagonist effects on striatal dopamine release: microdialysis studies in awake monkeys. Synapse 43:12-8

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