Loss of working memory, sensorimotor gating and other deficits in schizophrenic patients are improved by classic antipsychotic drugs, which block inhibitory G protein-coupled D2-like receptors. The therapeutic sites include the prefrontal cortex (PFC), the nucleus accumbens (Acb) and other forebrain regions that receive dopamine input from mesolimbic dopaminergic neurons within the ventral tegmental area (VTA). The Acb and ventral pallidum are important links in the PFC-thalamic circuitry, and each of these regions contains a subpopulation of cholinergic neurons that are activated not only by glutamate, but also by aversion-associated peptides interacting with neurokinin-1 (NK1) receptors. These cholinergic neurons are among those that express postsynaptic (dendritic) dopamine D2-like receptors, which are also potent presynaptic regulators of dopamine release. In rodent models, acute systemic administration of either D1/D2 (apomorphine) or D2/D3 (quinpirole) receptor agonists results in a sensorimotor gating deficit that can be measured by the diminished ability of prepulse auditory stimuli of low intensity to produce inhibition (PPI) of startle responses to intense auditory stimulation (AS). The disruption of PPI is opposed not only by D2 receptor blocking drugs, but also by other pharmacological or genetic manipulations that modulate either NMDA-dependent glutamate or nicotinic acetylcholine receptor (nAchR)-mediated cholinergic transmission. In this renewal grant application, electron microscopic immunolabeling (rat and mouse), and spatial-temporal gene deletion of the essential NR1 subunit of the NMDA receptor (mouse) will be used to answer fundamental question regarding the in vivo distribution and trafficking of neurotransmitter receptors when challenged by acute sensory stimuli or dopamine receptor agonists. The central hypothesis is that agonist availability and activity in opposing receptor systems determine the in vivo location and/or phosphorylation state of receptor proteins in the limbic forebrain and VTA.
Specific Aims 1 -2 will determine whether acute systemic administration of dopamine receptor agonists and AS affect the subcellular distribution or phosphorylation of NR1 in a manner that correlates with the content of D1 or D2 receptors in the Acb.
Aim 3 will test the hypothesis that quinpirole and AS also can produce changes in D2 receptor surface distributions in Acb spiny neurons, cholinergic interneurons, and/or dopamine terminals expressing the dopamine transporter (DAT).
Aim 4 will extend the analysis of the functional links between dopamine and acetylcholine by examining whether (1) D2 receptors in the VTA or PFC show either intracellular or synaptic associations with the alpha7-nAchR, a genetically defective subtype found in schizophrenic populations, and (2) whether the cholinergic neurons in the ventral pallidum are among those in which apomorphine and/or AS can affect the post-synaptic dendritic distribution of NK1 receptors. The proposed research will provide information that is essential for understanding and developing new strategies for treating schizophrenia and possibly other psychiatric disorders. NARRATIVE Schizophrenic patients show cognitive deficits and an inability to filter irrelevant sensory information, both of which reflect abnormalities in key neural networks within selective brain regions. Rodents show notable changes in sensory gating after perturbations of dopamine and other neurotransmitters in the brain regions that are most implicated in schizophrenia. The studies proposed in this renewal grant application will use rodent models and high resolution microscopic methods that are not possible in human brain, but have direct applicability to better understanding the treatment of schizophrenia and possibly other psychiatric diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH040342-28
Application #
8264206
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Nadler, Laurie S
Project Start
1985-09-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
28
Fiscal Year
2012
Total Cost
$336,798
Indirect Cost
$136,323
Name
Weill Medical College of Cornell University
Department
Neurology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Gan, J O; Bowline, E; Lourenco, F S et al. (2014) Adolescent social isolation enhances the plasmalemmal density of NMDA NR1 subunits in dendritic spines of principal neurons in the basolateral amygdala of adult mice. Neuroscience 258:174-83
Glass, Michael J; Robinson, Danielle C; Waters, Elizabeth et al. (2013) Deletion of the NMDA-NR1 receptor subunit gene in the mouse nucleus accumbens attenuates apomorphine-induced dopamine D1 receptor trafficking and acoustic startle behavior. Synapse 67:265-79
Garzon, Miguel; Pickel, Virginia M (2013) Somatodendritic targeting of M5 muscarinic receptor in the rat ventral tegmental area: implications for mesolimbic dopamine transmission. J Comp Neurol 521:2927-46
Fitzgerald, M L; Mackie, K; Pickel, V M (2013) The impact of adolescent social isolation on dopamine D2 and cannabinoid CB1 receptors in the adult rat prefrontal cortex. Neuroscience 235:40-50
Garzon, M; Duffy, A M; Chan, J et al. (2013) Dopamine Dýýý and acetylcholine *7 nicotinic receptors have subcellular distributions favoring mediation of convergent signaling in the mouse ventral tegmental area. Neuroscience 252:126-43
Fitzgerald, Megan L; Shobin, Eli; Pickel, Virginia M (2012) Cannabinoid modulation of the dopaminergic circuitry: implications for limbic and striatal output. Prog Neuropsychopharmacol Biol Psychiatry 38:21-9
Duffy, Aine M; Fitzgerald, Megan L; Chan, June et al. (2011) Acetylcholine *7 nicotinic and dopamine D2 receptors are targeted to many of the same postsynaptic dendrites and astrocytes in the rodent prefrontal cortex. Synapse 65:1350-67
Fitzgerald, Megan L; Lupica, Carl R; Pickel, Virginia M (2011) Decreased parvalbumin immunoreactivity in the cortex and striatum of mice lacking the CB1 receptor. Synapse 65:827-31
Hill, Matthew N; McLaughlin, Ryan J; Pan, Bin et al. (2011) Recruitment of prefrontal cortical endocannabinoid signaling by glucocorticoids contributes to termination of the stress response. J Neurosci 31:10506-15
Coleman, Christal G; Wang, Gang; Park, Laibaik et al. (2010) Chronic intermittent hypoxia induces NMDA receptor-dependent plasticity and suppresses nitric oxide signaling in the mouse hypothalamic paraventricular nucleus. J Neurosci 30:12103-12

Showing the most recent 10 out of 113 publications