Abstract
Chronic blockade of dopamine D2 receptors, a common mechanism of action for antipsychotic drugs, down-regulates D1 receptors in the prefrontal cortex and, as shown here, produces severe impairments in working memory. These deficits were reversed in monkeys by short-term coadministration of a D1 agonist, ABT 431, and this improvement was sustained for more than a year after cessation of D1 treatment. These findings indicate that pharmacological modulation of the D1 signaling pathway can produce long-lasting changes in functional circuits underlying working memory. Resetting this pathway by brief exposure to the agonist may provide a valuable strategy for therapeutic intervention in schizophrenia and other dopamine dysfunctional states.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antipsychotic Agents / pharmacology*
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Cyclic AMP / metabolism
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Dopamine / metabolism
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Dopamine Agonists / pharmacology*
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Dopamine Antagonists / pharmacology
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Down-Regulation
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Female
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Haloperidol / pharmacology*
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Haplorhini
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Memory / drug effects*
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Prefrontal Cortex / drug effects
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Prefrontal Cortex / metabolism
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Psychomotor Performance / drug effects
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Pyridines / pharmacology*
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Receptors, Dopamine D1 / agonists
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Receptors, Dopamine D1 / metabolism*
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Signal Transduction
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Tetrahydronaphthalenes / pharmacology*
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Time Factors
Substances
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Antipsychotic Agents
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Dopamine Agonists
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Dopamine Antagonists
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Pyridines
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Receptors, Dopamine D1
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Tetrahydronaphthalenes
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adrogolide hydrochloride
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Cyclic AMP
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Haloperidol
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Dopamine