Claims
- 1. A transgenic non-human animal having a transgene comprising a leucine-to-serine mutation of the α4 nicotinic receptor subunit chromosomally integrated into germ cells of the animal.
- 2. The transgenic non-human animal of claim 1, wherein the leucine to serine mutation is located in the M2 region at 4′.
- 3. The transgenic non-human animal of claim 1, wherein the animal is selected from murine, bovine, ovine, avian or piscine.
- 4. The transgenic non-human animal of claim 1, wherein the animal is heterozygous for the mutation of the α4 nicotinic receptor subunit gene.
- 5. A transgenic mouse comprising a transgene having a leucine-to-serine mutation at 9′ of the α4 nicotinic receptor subunit, wherein expression of the receptor subunit gene results in a mouse that displays modified behavior compared to a normal mouse.
- 6. The mouse of claim 5, wherein the mouse displays nicotinic hypersensitivity, increased anxiety, poor motor learning, excessive ambulation, displays a reduction in dopaminergic neuron function upon aging, susceptibility to seizure, spontaneous seizure, or any combination thereof.
- 7. A method for producing a transgenic mouse having a modified behavior compared to a normal mouse, comprising
(a) introducing a transgene comprising a selectable marker sequence into a mouse embryonic stem cell; (b) introducing said mouse embryonic stem cell into a mouse embryo; (c) transplanting said embryo into a pseudopregnant mouse; (d) allowing said embryo to develop to term; and (e) identifying a transgenic mouse whose genome comprises a disruption of the endogenous α4 nicotinic receptor subunit gene, wherein the disruption results in the mouse having a modified behavior compared to a normal mouse.
- 8. A transgenic mouse produced by the method of claim 7, wherein the genome of the mouse comprises a disruption of the endogenous α4 nicotinic receptor subunit, wherein the disruption results in the mouse having a leucine to serine mutation of the α4 nicotinic receptor subunit as compared to a wild-type mouse.
- 9. The transgenic mouse of claim 8, wherein the transgenic mouse is heterozygous for the disruption of the endogenous α4 nicotinic receptor gene.
- 10. The transgenic mouse of claim 7, wherein the mouse displays nicotinic hypersensitivity, increased anxiety, poor motor learning, excessive ambulation, a reduction in dopaminergic neuron function upon aging, or any combination thereof.
- 11. A method for screening a candidate agent for the ability to modulate nicotine-mediated behavior in the transgenic animal of claim 1 comprising:
(a) administering to a first transgenic animal of claim 1 a candidate agent, and (b) comparing nicotine-mediated behavior of the first transgenic animal to the nicotine-mediated behavior of a second transgenic animal of claim 1 not administered the candidate agent; wherein a difference in nicotine-mediated behavior in the first transgenic animal administered the candidate agent compared to the second transgenic animal not administered the candidate agent is indicative of a candidate agent that modifies nicotine-mediated behavior.
- 12. The method of claim 11, wherein the nicotine-mediated behavior is anxiety.
- 13. The method of claim 12, wherein the difference in nicotine-mediated behavior is decreased anxiety compared to the second transgenic animal.
- 14. The method of claim 11, wherein the nicotine-mediated behavior is ambulation.
- 15. The method of claim 14, wherein the difference in nicotine-mediated behavior is decreased ambulation compared to the second transgenic animal.
- 16. The method of claim 11, wherein the nicotine-mediated behavior is motor learning.
- 17. The method of claim 16, wherein the difference in nicotine-mediated behavior is improved motor learning compared to the second transgenic animal.
- 18. The method of claim 11, wherein the nicotine-mediated behavior is susceptibility to seizure.
- 19. The method of claim 11, wherein the mouse displays spontaneous seizures.
- 20. A method of screening for candidate agent that modulates nicotine hypersensitivity comprising:
(a) administering a candidate agent to a transgenic animal of claim 1;(b) determining the effect of the agent upon a cellular or molecular process associated with nicotinic hypersensitivity compared to an effect of the agent administered to a non-transgenic animal, wherein a difference in effect is indicative of an agent that modulates nicotine hypersensitivity.
- 21. The method of claim 20, wherein the cellular or molecular process associated with nicotinic hypersensitivity is dopaminergic neuronal cell loss.
- 22. A method of screening for a candidate agent that modulates that modulates seizure activity associated with epilepsy, comprising
(a) administering a candidate agent to a transgenic animal of claim 1;(b) determining the effect of the agent upon seizure activity associated with epilepsy compared to an effect of the agent administered to a non-transgenic animal, wherein a difference in effect is indicative of an agent that modulates seizure activity associated with epilepsy.
RELATED APPLICATIONS
[0001] This application claims the benefit of priority under 35 U.S.C. §119 of Provisional Application No. 60/230,757, filed Sep. 7, 2000, incorporated herein in its entirety.
ACKNOWLEDGEMENT OF FEDERAL GOVERNMENT SUPPORT
[0002] This application was supported by Grant Numbers NS-1 1756, MH-49176, and DA11836, awarded by the National Institutes of Health. The Government may have certain rights in the invention.
Provisional Applications (1)
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Number |
Date |
Country |
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60230757 |
Sep 2000 |
US |