Impaired D2 dopamine receptor function in mice lacking type 5 adenylyl cyclase

초록

Dopamine receptor subtypes, D1 and D2, are co-localized in the striatum, but have been envisioned to stimulate or inhibit adenylyl cyclases (ACs) to produce distinct physiological and pharmacological responses. However, the identity of the AC isoform that is coupled to the specific dopamine receptor subtype in the brain remains unknown. To specify the in vivo role of the type 5 adenylyl cyclase (AC5), a candidate effector for dopamine receptors, we generated mice deficient for the AC5 gene. In the absence of AC5, the D1/AC system was functional because of the presence of additional ACs, whereas the D2/AC system was completely impaired. Being consistent with the defective D2/AC function, D2 dependent D1 inhibition was absent in AC5-/-, and AC5-/- mice are blunt to cataleptic doses of antipsychotic drugs, haloperidol and sulpiride. However, AC5-/- mice did not display reduction of the spontaneous motor behaviors observed in D2-/- mice. These results suggest that the signals from D1 and D2 receptors could be converged on AC5, and also diverged at the level of AC5, in which AC5 is essential for antipsychotic drugs, but not necessary for spontaneous motor behaviors.