This proposal addresses basic questions concerning the electrophysiological and molecular pharmacological mechanisms of the recently identified and essentially uncharacterized heterogeneous populations of nicotinic acetylcholine receptors (AChRs) located in various regions of the brain. The precise knowledge of the functional properties of such an elusive receptor is of major significance for the understanding of the physiology of the brain under normal conditions and in disease states. The novel neurotoxin (+) anatoxin-a (AnTX) and its synthetic analogs including the (-) enantiomer have proven essential to uncover the structural requirements for agonism at the muscle AChR. Furthermore, by virtue of its potency and specificity, (+)AnTX has enabled the recording of AChR currents in the central nervous system (CNS) and to reveal a great degree of heterogeneity of the AChRs, both within the same cell and among different cell types. Thus, the new long-term goal of this project is to investigate the fundamental functional and pharmacological properties of the AChR at different stages of development and under conditions of chronic exposure to selected drugs. In addition to ACh and the AnTX analogs, other selected weak agonists with similar specificity will be used to investigate AChR responses in the CNS. The noncompetitive antagonists that have been documented for the peripheral AChR will now be studied in the CNS, including a novel series of acridine araphane analogs which function as sensitive """"""""rulers"""""""" to define the antagonist sites on the AChR. The effects of these selective toxins will also be studied at the N-methyl-D-aspartate receptor because of the great deal of structural and functional homology that has been observed with peripheral and central AChR. These studies are essential for the understanding of the interrelationships of homologous ligand-gated channels and related disease states such as Alzheimer's dementia. The proposed experiments will utilize a variety of electrophysiological techniques, including a new fast drug perfusion and withdrawal system developed in this laboratory, coupled with ligand binding, fluorescence labelling, and kinetic studies of receptors, and morphological studies of acutely dissociated and tissue cultured neuronal cells to reveal the basic mechanisms underlying the function of these different forms of AChR.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS025296-05
Application #
3410557
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1987-07-01
Project End
1998-03-31
Budget Start
1992-04-01
Budget End
1993-03-31
Support Year
5
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Alkondon, Manickavasagom; Pereira, Edna F R; Todd, Spencer W et al. (2015) Functional G-protein-coupled receptor 35 is expressed by neurons in the CA1 field of the hippocampus. Biochem Pharmacol 93:506-18
Banerjee, Jyotirmoy; Alkondon, Manickavasagom; Albuquerque, Edson X et al. (2013) Contribution of CA3 and CA1 pyramidal neurons to the tonic *7 nAChR-dependent glutamatergic input to CA1 pyramidal neurons. Neurosci Lett 554:167-71
Albuquerque, Edson X; Schwarcz, Robert (2013) Kynurenic acid as an antagonist of ýý7 nicotinic acetylcholine receptors in the brain: facts and challenges. Biochem Pharmacol 85:1027-32
Banerjee, Jyotirmoy; Alkondon, Manickavasagom; Pereira, Edna F R et al. (2012) Regulation of GABAergic inputs to CA1 pyramidal neurons by nicotinic receptors and kynurenic acid. J Pharmacol Exp Ther 341:500-9
Wang, Xiao-Dan; Notarangelo, Francesca M; Wang, Ji-Zuo et al. (2012) Kynurenic acid and 3-hydroxykynurenine production from D-kynurenine in mice. Brain Res 1455:1-9
Notarangelo, Francesca M; Wu, Hui-Qiu; Macherone, Anthony et al. (2012) Gas chromatography/tandem mass spectrometry detection of extracellular kynurenine and related metabolites in normal and lesioned rat brain. Anal Biochem 421:573-81
Pocivavsek, Ana; Wu, Hui-Qiu; Elmer, Greg I et al. (2012) Pre- and postnatal exposure to kynurenine causes cognitive deficits in adulthood. Eur J Neurosci 35:1605-12
Banerjee, Jyotirmoy; Alkondon, Manickavasagom; Albuquerque, Edson X (2012) Kynurenic acid inhibits glutamatergic transmission to CA1 pyramidal neurons via ?7 nAChR-dependent and -independent mechanisms. Biochem Pharmacol 84:1078-87
Pocivavsek, Ana; Wu, Hui-Qiu; Potter, Michelle C et al. (2011) Fluctuations in endogenous kynurenic acid control hippocampal glutamate and memory. Neuropsychopharmacology 36:2357-67
Alkondon, Manickavasagom; Pereira, Edna F R; Albuquerque, Edson X (2011) Endogenous activation of nAChRs and NMDA receptors contributes to the excitability of CA1 stratum radiatum interneurons in rat hippocampal slices: effects of kynurenic acid. Biochem Pharmacol 82:842-51

Showing the most recent 10 out of 104 publications