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

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 A_2A receptor agonists in striatum. However, D₁- or A_2A-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 A_2A in striatum and the cascade involving AC5 among diverse D₂ signaling pathways is essential for neuroleptic effects of antipsychotic drugs.