The Action of Neuroleptic Drugs on Dopamine-Stimulated Adenosine Cyclic 3',5'-Monophosphate Production in Rat Neostriatum and Limbic Forebrain

Abstract

Neuroleptic drugs of various types were more potent inhibitors of dopamine-sensitive production of adenosine cyclic 39,59-monophosphate in homogenates of rat brain striatum than non-neuroleptic drugs of similar structures. The most potent drugs were phenothiazines and thioxanthenes with a -CF3 group in position 2 of the tricyclic system and a piperazino side chain. There were also large differences in the effects of cis and trans isomers of thioxanthenes in which the 2-substituent and the side chain are on the same or opposite side of the double bond connecting the side chain to the ring system. Thus α-flupenthixol, α-clopenthixol, and α-chlorprothixene, which are the cis isomers, were considerably more potent than the corresponding β-isomers of the same drugs. α-Flupenthixol was also considerably more potent than the β-isomer in antagonizing the effect of dopamine on cyclic AMP production in the olfactory tubercle and nucleus accumbens, and in antagonizing the potent dopamine agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene in the striatum. These results are discussed in relation to the hypothesis that neuroleptic activity may be related to the blockade of dopamine receptors in the central nervous system.