Dopamine transporter knockout mice

Details Dopamine transporter knockout mice Dopamine transporter knockout mice

1998-08-14

2001-04-17

Clark, Deborah J. R. (Department: 1633)

Multicellular living organisms and unmodified parts thereof and

Method of using a transgenic nonhuman animal in an in vivo...

C800S009000, C800S018000, C800S025000

Reexamination Certificate

active

06218595

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to methods of increasing spontaneous motor activity in a subject in need of such treatment, particularly subjects afflicted with Parkinson's disease or tardive dyskinesis.
BACKGROUND OF THE INVENTION
Dopamine is involved in the control of motor function, cognition and affect (A. Dahlstrom and K. Fuxe,
Acta Physiol. Scand.
232, 1-55 (1965); U. Ungerstedt,
Acta Physiol. Scand.
367, 1-48 (1970)). Imbalance in the dopamine system is believed to be involved in such conditions as schizophrenia (T. Crow,
Brit. J. Psychiatry
137, 383-386 (1980); Filbiger, in: The Mesolimbic dopamine system: From motivation to action, 615-37 (Eds. P. Willner and J. Scheel-Krger (1991)), Parkinson's disease (H. Ehringer and O. Hornykiewitz,
Klin. Wochenschr.
38, 1236-1239 (1960), tardive dyskinesia and drug addiction (R. Wise and P. P. Rompre,
Ann. Rev. Psychol.
40, 191-225 (1989); G. Koob and F. Bloom,
Science
242, 715-723 (1988); G. DiChiara et al.,
Proc. Natl Acad. Sci. U.S.A.
85, 5272-5278 (1998)).
The dopamine transporter, a member of the large family of Na
+
/Cl
−
dependent transporters, aids in terminating dopaminergic neurotransmission by rapid re-uptake of dopamine (B. Giros and M. Caron,
Trends Pharmacol. Sci.
14, 43-49 (1993). It is a major target of the psychostimulant drugs cocaine and amphetamine (B. Giros and M. Caron,
Trends Pharmacol. Sci.
14, 43-49 (1993); M. Ritz et al.,
Science
237, 1219-1223 (1987)), but its overall role in vivo is still poorly understood.
SUMMARY OF THE INVENTION
A first aspect of the present invention is a recombinant rodent comprising cells containing a pair of genomic dopamine transporter protein alleles, and wherein at least one of said alleles is incapable of expressing endogenous dopamine transporter protein. The rodent may be a homozygote, where both of said alleles are incapable of expressing endogenous dopamine transporter protein, or the rodent may be heterozygote, and one of said alleles expresses endogenous dopamine transporter protein.
A further aspect of the present invention is a method of upregulating spontaneous motor activity in a subject in need of such treatment. The method comprises inhibiting dopamine transporter function (i.e., dopamine reuptake mediated by the dopamine transporter protein) in the subject by an amount effective to enhance spontaneous motor activity in that subject. The method may be carried out by any suitable means, such as by administering a dopamine transporter blocker to said subject in an amount effective to enhance spontaneous motor activity. Suitable subjects include those afflicted with Parkinson's disease and those afflicted with tardive dyskinesia, particularly drug-induced tardive dyskinesia.
A still further aspect of the present invention is the use of a dopamine transporter inhibitor for the preparation of a medicament for enhancing spontaneous motor activity in that subject, as described above.


REFERENCES:
patent: 5866756 (1999-02-01), Giros et al.
Bradley et al. Modifying the Mouse: Design and Desire. Bio/Technology, vol. 10, pp. 534-539, May 1992.*
Fassler et al. Knockout Mice: How to Make Them and Why. The Immunological Approach. Int. Arch. Allergy Immunol., vol. 106, pp. 323-334, 1995.

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