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Nicotine in the Brain

Institution: University of California, San Diego
Investigator(s): Darwin Berg, Ph.D.
Award Cycle: 2000 (Cycle 9) Grant #: 9RT-0221 Award: $518,966
Subject Area: Nicotine Dependence
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Cigarette smoking is the leading cause of premature deaths in the United States. Nicotine has been identified as the principal addictive component in tobacco smoke driving this pathological behavior. To achieve its effects, nicotine interacts with a family of specific membrane components that function as receptors for the naturally occurring neurotransmitter acetylcholine (ACh). It is now clear that so-called nicotinic receptors exert multiple effects at the cellular level and participate in a variety of higher order brain functions; the receptors have also been implicated in a number of neurodegenerative diseases. In addition to excessive activation of the receptors, chronic nicotine exposure can impose long-term regulatory effects on them. The physiological consequences of these effects represent pressing biomedical questions that remain unanswered.

One of the most interesting and abundant nicotinic receptors in brain is a species composed of subunits called the 7. Recent results indicate that 7 receptors perform a host of functions in the nervous system, including the modulation of electrical signals at synapses and the developmental regulation of calcium-dependent events in neurons. The receptors are known to be widely distributed throughout the cortex of the brain. The present experiments employ an animal model to examine the properties of 7 receptors in the mammalian brain, to determine their significance for signaling, and to elucidate the impact of chronic nicotine exposure both on receptor function and on the neuronal circuits in which the receptors participate. The experimental approaches will combine electrical recording techniques, biochemical binding experiments, and fluorescence imaging.

The expected results will provide new information about the physiological significance of 7 nicotinic receptors in the cortex of the brain, and will indicate the kinds of compensatory changes expressed by cortical neurons to mitigate the prolonged excessive stimulation produced by chronic nicotine exposure. This information may also be of value in the search for therapeutic strategies to combat the cortical effects of nicotine. One strategy may be the design of appropriate drugs for targeting the receptors and influencing their activity levels in desired directions for either negating or overcoming the changes caused by tobacco usage.
Publications

Synaptically-driven calcium transients via nicotinic receptors on somatic spines
Periodical: Journal of Neuroscience Index Medicus:
Authors: Shoop RD, Chang KT, Ellisman MH, Berg DK ART
Yr: 2001 Vol: 21 Nbr: Abs: Pg: 771-781

Beta-amyloid peptide blocks the response of alpha7-containing nicotinic receptors on hippocampal neurons
Periodical: Proceedings of the National Academy of Sciences of the United States of America Index Medicus:
Authors: Liu Q-s, Kawai H, Berg DK ART
Yr: 2001 Vol: 98 Nbr: Abs: Pg: 4734-4739

Dramatic potentiation of nicotinic responses from alpha7-containing acetylcholine receptors by select albumins
Periodical: Society for Neuroscience Abstracts Index Medicus:
Authors: Conroy WG, Liu Q-S, Berg D.K ABS
Yr: 0 Vol: Nbr: Abs: Pg:

Nicotinic acetylcholine receptors containing alpha-7 subunits do not undergo long-lasting inactivation even when up-regulated by chronic nicotine exposure.
Periodical: Journal of Neurochemistry Index Medicus:
Authors: Kawai H, Berg DK ART
Yr: 2001 Vol: 78 Nbr: Abs: Pg: 1367-1378

Beta-amyloid peptide blocks the response of alpha-7-containing nicotinic receptors on hippocampal neurons.
Periodical: Proceedings of the National Academy of Sciences of the United States of America Index Medicus:
Authors: Liu Q, Kawai H, Berg DK ART
Yr: 2001 Vol: 98 Nbr: Abs: Pg: 4734-4739

Voltage-gated channels block nicotinic regulation of CREB phosphorylation and gene expression in neurons.
Periodical: Neuron Index Medicus:
Authors: Chang K, Berg DK ART
Yr: 2001 Vol: 32 Nbr: Abs: Pg: 855-865

Ultrastructure of a somatic spine mat for nicotinic signaling in neurons.
Periodical: Journal of Neuroscience Index Medicus:
Authors: Shoop RD, Esquenazi E, Yamada N, Ellisman MH, Berg DK ART
Yr: 2002 Vol: 22 Nbr: Abs: Pg: 748-756

Nicotinic alpha-7 receptors: synaptic options and down-stream signaling in neurons.
Periodical: Journal of Neuroscience Index Medicus:
Authors: Berg DK, Conroy WG ART
Yr: 2002 Vol: 53 Nbr: Abs: Pg: 512-523

Maturation of postsynaptic nicotinic structures on autonomic neurons requires innervation but not cholinergic transmission.
Periodical: European Journal of Neuroscience Index Medicus:
Authors: Kaiser S, Blank M, Berg DK ART
Yr: 2002 Vol: 16 Nbr: Abs: Pg: 1-10

Nicotinic alpha-7 receptor clusters on hippocampal GABAergic neurons: regulation by synaptic activity and neurotrophins.
Periodical: Journal of Neuroscience Index Medicus:
Authors: Kawai H, Zago W, Berg DK ART
Yr: 2002 Vol: 22 Nbr: Abs: Pg: 7903-7912

Nicotinic regulation of CREB activation in hippocampal neurons by glutamatergic and non0glutamatergic pathways.
Periodical: Molecular Cell Neuroscience Index Medicus:
Authors: Hu M, Liu Qs, Chang KT, Berg DK ART
Yr: 2002 Vol: 21 Nbr: Abs: Pg: 616-625

PDZ-containing proteins provide a functional postsynaptic scaffold for nicotinic receptors in neurons.
Periodical: Neuron Index Medicus:
Authors: Conroy WG, Liu Z, Nai Q, Coggan JS, Berg DK ART
Yr: 2003 Vol: 38 Nbr: Abs: Pg: 759-771

Large clusters of alpha-7-containing nicotinic acetylcholine receptors on chick spinal cord neurons.
Periodical: Journal of Comparative Neurology Index Medicus:
Authors: Roth AL, Berg DK ART
Yr: 2003 Vol: Nbr: Abs: Pg: