Dopamine neurons that project from the midbrain to cortical and limbic structures modulate attention and information processing functions and contribute to the organization of locomotor behavior. Related behaviors are impaired in patients with schizophrenia and other psychiatric disorders, suggesting that alterations in mesocorticolimbic dopamine signaling have pathophysiological relevance in human diseases. D1-like and D2-like dopamine receptors have been implicated in the normal activity of these dopaminergic circuits. The functional distinctions among the 3 cloned members of the D2-like subfamily (D2, D3, and D4) remain elusive, in part because of the limited specificity of pharmacological ligands. Strains of gene knockout mice that lack either the D2, D3, or D4 receptors have been generated as genetic models to understand the functions, at a systems level, of these multiple independent genes. Initial characterizations reveal that the individual receptor knockout strains have many unique behavioral phenotypes, including changes in locomotor behavior and startle response measures of sensorimotor gating deficits seen in schizophrenia. The general hypothesis to be tested is that the D2-like receptor subtypes have selective functional roles in the dopaminergic modulation of information processing, locomotor activity, and the sequential organization of behavior.
The specific aims to address this hypothesis are: (1) generate congenic C57BL/6 strains of mutant mice with individual D2, D3, or D4 dopamine receptor knockouts and all permutations of double and triple receptor mutations; (2) characterize the phenotype of each strain of homozygous and heterozygous mice using measures of the amount and patterns of locomotor activity, the response to a novel object, and startle reactivity, habituation, and prepulse inhibition; (3) characterize the effects of amphetamine and selected direct dopamine agonists on the same measures; (4) characterize the effects of amphetamine and selected direct dopamine agonists on patterns of locomotor and exploratory behavior in each of the mutant strains; and (5) characterize the effects of amphetamine and selected direct dopamine agonists on startle reactivity, habituation, and prepulse inhibition in each of the mutant strains of mice. These phenotypic and pharmacological comparisons of D2-subtype knockouts in congenic strains having a common genetic background will provide fundamental information regarding the specific functional roles of D2-like receptors in the regulation of unconditioned behaviors that have particular relevance to both psychotic disorders and psychostimulant abuse. This information will have important implications for the further development of therapeutic approaches to the treatment of both schizophrenia and drug abuse.
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