Reversal of antipsychotic-induced working memory deficits by short-term dopamine D1 receptor stimulation.
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.
Castner
S A
SA
Section of Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
Williams
G V
GV
Goldman-Rakic
P S
PS
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D006220:Haloperidol / Q000494:pharmacology*; D000882:Haplorhini; D008568:Memory / Q000187:drug effects*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011597:Psychomotor Performance / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013997:Time Factors
D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D011725:Pyridines; D017447:Receptors, Dopamine D1; D013764:Tetrahydronaphthalenes; C095428:adrogolide hydrochloride; D000242:Cyclic AMP; D006220:Haloperidol; D004298:Dopamine