INTERACTION OF FORMAMIDINES WITH OCTOPAMINE-SENSITIVE DOPAMINE-SENSITIVE AND 5-HYDROXYTRYPTAMINE-SENSITIVE ADENYLATE-CYCLASE IN THE NERVE CORD OF PERIPLANETA-AMERICANA

The interaction of chlordimeform, N1-demethylchlordimeform [N2-(4-chloro-o-tolyl)-N1-methylformamidine], BTS-27271 [N1-methyl-N2-(2,4-xylyl)formamidine, the 2,4-xylyl analogue of N1-demethylformamidine], and amitraz with octopamine-, dopamine-, and 5-hydroxytryptamine-mediated enhancement of cyclic-AMP production was investigated in nerve cord homogenates of the American cockroach Periplaneta americana. N1-Demethylchlordimeform, BTS-27271 and amitraz simulated the actions of the monoamines in enhancing cyclic-AMP production, whereas chlordimeform showed no such agonism. Additivity studies indicated that these formamidine derivatives were interacting with dopamine- and 5-hydroxytryptamine-sensitive sites, in addition to their known interaction with octopamine-sensitive adenylate cyclase. N1-Demethylchlordimeform (Ki = 0.2 .mu.M) and amitraz (Ki = 0.5 .mu.M) inhibited the dopamine-mediated response, but only N1-demethylchlordimeform (Ki = 2.mu.M) effected appreciable inhibition of the octopamine-response. Pharmacological characterisation of the formamidine-induced elevation of cyclic-AMP production indicated that the agonistic effects of formamidines are expressed primarily through the octopamine-sensitive adenylate cyclase, rather than the dopamine- or 5-hydroxytryptamine-sensitive sites. The results are discussed in the light of the proposal that the bahavioral changes, associated with formamidine poisoning, reflect the cumulative effects of octopamine-agonism, and antagonism of the dopamine- and 5-hydroxytryptamine-mediated processes.