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The Journal of Neuroscience, November 15, 2000, 20(22):8305-8314
Dopamine D2 Long Receptor-Deficient Mice Display Alterations in
Striatum-Dependent Functions
Yanyan
Wang1,
Rong
Xu1,
Toshikuni
Sasaoka2,
Susumu
Tonegawa3,
Mei-Ping
Kung4, and
Emma-Betty
Sankoorikal1
Departments of 1 Pharmacology and
4 Radiology, University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania 19104-6084, 2 Division of
Cortical Function Disorders, National Institute of Neuroscience, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan, and 3 Howard
Hughes Medical Institute and Department of Biology, Massachusetts
Institute of Technology, Cambridge, Massachusetts 02139
The dopamine D2 receptor (D2) system has been implicated in several
neurological and psychiatric disorders, such as schizophrenia and
Parkinson's disease. There are two isoforms of the D2 receptor: the
long form (D2L) and the short form (D2S). The two isoforms are
generated by alternative splicing of the same gene and differ only by
29 amino acids in their protein structures. Little is known about the
distinct functions of either D2 isoform, primarily because selective
pharmacological agents are not available. We generated D2L
receptor-deficient (D2L /) mice by making a subtle mutation in the
D2 gene. D2L/ mice (which still express functional D2S) displayed
reduced levels of locomotion and rearing behavior. Interestingly,
haloperidol produced significantly less catalepsy and inhibition of
locomotor activity in D2L/ mice. These findings suggest that D2L
and D2S may contribute differentially to the regulation of certain
motor functions and to the induction of the extrapyramidal side effects
associated with the use of typical antipsychotic drugs (e.g.,
haloperidol). Quinpirole induced a similar initial suppression of
locomotor activity in both D2L/ and wild-type mice. In addition,
the D2S receptor in the mutant mice functioned approximately equally
well as did D2L as an impulse-modulating autoreceptor. This suggests
that the functions of these two isoforms are not dependent on the
formation of receptor heterodimers. Our findings may provide novel
information for potentially developing improved antipsychotic drugs.
Key words:
dopamine D2L receptor; knock-out mice; locomotion; catalepsy; autoreceptor; haloperidol; D2S receptor
Copyright © 2000 Society for Neuroscience 0270-6474/00/20228305-10$05.00/0
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