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.
Russi
G
G
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Girotti
P
P
Cadoni
C
C
Di Chiara
G
G
Consolo
S
S
D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003956:Dialysis; D004298:Dopamine / Q000378:metabolism; D005260:Female; D008781:Methyltyrosines / Q000494:pharmacology; D017551:Microdialysis; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000187:drug effects*; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D017330:Remoxipride / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors; D019805:alpha-Methyltyrosine
D014150:Antipsychotic Agents; D001552:Benzazepines; D008781:Methyltyrosines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D017330:Remoxipride; D019805:alpha-Methyltyrosine; D014446:Tyrosine 3-Monooxygenase; D000109:Acetylcholine; D004298:Dopamine