The heaviest smoking populations in the US include patients with schizophrenia (SZ). Research indicates that nicotine may constitute an important form of self-medication for such patients, particularly in its effects on the pathognemonic deficits of sensory-gating. Recent studies demonstrate a higher degree of dependence on nicotine in SZ vs. control populations. Genetic variations in the alpha 7 nicotinic acetylcholine receptor (a7*-nAChR) are linked with the sensory gating deficits associated with SZ. Likewise, genetic variants of Neuregulin 1 (Nrg1), a key regulator of (a7*-nAChRs), have recently been associated with heritab e forms of SZ. These observations prompt our proposal of convergent effects on Nrg1 and a7*-expression in the co-morbidity of nicotine abuse and susceptibility to neuropsychiatric disorders such as SZ. CEBRA stage 1 funding is sought to initiate in vivo electrophysiology and behavioral studies in single and compound genetically-modified mice. The genetically altered lines to be examined include the isoform specific: Type Ill-Nrg1 heterozygous mutant (Nrg1) and the a7 nAChR subunit mutant Chrna7(). Proposed studies begin tests of the hypothesized convergence of Nrg1 and a7 regulation as heritable components of susceptibility to nicotine effects, tobacco dependence and facets of SZ phenotypes by comparison of mice prenatal nicotine exposure. Thus, the AIM of this STAGE 1 Application is to initiate tests of whether deficits in Nrg1 (with and without deficits in a7) alter the development, maintenance and/or plasticity of hippocampal-accumbens circuits in vivo. Assessment of genotype dependent changes in synaptic circuits and nicotine-induced excitability in intact systems examine ventral hippocampal-striatal interactions using in vivo intracellular and multi unit recordings. The impact of genetic profile on excitatory-input gating to the ventral striatum and on the effects of nicotine will be assessed in parallel behavioral studies and recordings from adult mice subjected to prenatal and/or acute nicotine exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA019941-02
Application #
7140266
Study Section
Special Emphasis Panel (ZDA1-MXS-M (01))
Program Officer
Rutter, Joni
Project Start
2005-09-05
Project End
2007-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
2
Fiscal Year
2006
Total Cost
$135,009
Indirect Cost
Name
New York State Psychiatric Institute
Department
Type
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032