Neuroleptics increase striatal acetylcholine release by a sequential D-1 and D-2 receptor mechanism

In normal striata, pre-treatment with the D-1 antagonist SCH 23390 (250 and 25 micrograms kg-1, s.c.) completely and lastingly prevented the D-2 antagonist remoxipride (REM) from increasing acetylcholine (ACh) release; post-treatment did not affect REM action. In alpha-methyl-p-tyrosine (alpha-MpT) dopamine (DA)-depleted striata, however, pretreatment with SCH 23390 resulted in a transient impairment of REM induced stimulation of ACh release but post-treatment still had no effect. Two different mechanisms therefore seem to be involved in D-2 antagonist-induced stimulation of ACh release; the antagonists indirectly activate a D-1 receptor-mediated facilitatory mechanism regulating cholinergic function, and directly block a D-2 receptor-mediated inhibitory one. In normal rats, in an early phase after D-2 antagonist administration, only the first mechanism is operative; in a later phase, both mechanisms cooperate in the stimulation of ACh release. When DA release is impaired by alpha-MpT, the D-2 inhibitory receptor mechanism becomes more important than the D-1 facilitatory one in controlling ACh release.