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The Journal of Neuroscience, September 15, 2002, 22(18):7931-7940

Impaired D2 Dopamine Receptor Function in Mice Lacking Type 5 Adenylyl Cyclase

Ko-Woon Lee1, 2, Jang-Hee Hong1, 3, In Young Choi1, Yongzhe Che4, Ja-Kyeong Lee4, Sung-Don Yang5, Chang-Woo Song5, Ho Sung Kang2, Jae-Heun Lee3, Jai Sung Noh6, Hee-Sup Shin7, and Pyung-Lim Han1

1 Department of Neuroscience and Ewha Institute of Neuroscience, Ewha Womans University School of Medicine, Seoul, 110-783, Korea, 2 Department of Molecular Biology, Pusan National University, Pusan, 609-735, Korea, 3 Department of Pharmacology, College of Medicine, Chungnam National University, Taejon, 301-747, Korea, 4 Department of Anatomy, Inha University School of Medicine, Inchon, 400-712, Korea, 5 Toxicology Research Group, Korea Research Institute of Chemistry and Technology, Taejon, 305-345, Korea, 6 Department of Psychiatry, Ajou University School of Medicine, Suwon, 442-721, Korea, and 7 National Creative Research Initiative Center for Calcium and Learning, Korea Institute of Science and Technology, Seoul, 136-791, Korea

Dopamine receptor subtypes D1 and D2, and many other seven-transmembrane receptors including adenosine receptor A2A, are colocalized in striatum of brain. These receptors stimulate or inhibit adenylyl cyclases (ACs) to produce distinct physiological and pharmacological responses and interact with each other synergistically or antagonistically at various levels. The identity of the AC isoform that is coupled to each of these receptors, however, remains unknown. To investigate the in vivo role of the type 5 adenylyl cyclase (AC5), which is preferentially expressed in striatum, mice deficient for the AC5 gene were generated. The genetic ablation of the AC5 gene eliminated >80% of forskolin-induced AC activity and 85-90% of AC activity stimulated by either D1 or A2A receptor agonists in striatum. However, D1- or A2A-specific pharmaco-behaviors were basically preserved, whereas the signal cascade from D2 to AC was completely abolished in AC5-/-, and motor activity of AC5-/- was not suppressed by treatment of cataleptic doses of the antipsychotic drugs haloperidol and sulpiride. Interestingly, both haloperidol and clozapine at low doses remarkably increased the locomotion of AC5-/- in the open field test that was produced in part by a common mechanism that involved the increased activation of D1 dopamine receptors. Together, these results suggest that AC5 is the principal AC integrating signals from multiple receptors including D1, D2, and A2A in striatum and the cascade involving AC5 among diverse D2 signaling pathways is essential for neuroleptic effects of antipsychotic drugs.

Key words: AC5; dopamine receptors; knock-out mice; antipsychotics; striatum; adenylyl cyclase; cAMP; adenosine receptors

Copyright © 2002 Society for Neuroscience  0270-6474/02/22187931-10$05.00/0


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