Basic research indicates a role for dopamine (DA) D1 antagonism in the treatment of
schizophrenia. Clinical trials have not confirmed any role. Besides the defining second
messenger (adenylyl cyclase [AC]), DA D1 receptors are linked to other effectors (e.g.,
phospholipase C [PLC]). Differing actions of DA D1 antagonists upon differing effectors
could explain conflicting results between the lab/clinic.
In a monkey model in which behavioral effects of DA D1 antagonists/agonists have been
well characterized we examined: 1) SKF 83959, biochemically, a DA D1 antagonist, behaviorally
a DA D1 agonist, and 2) SKF 83822, biochemically, a DA D1 agonist, which, unlike all
previously tested DA D1 agonists, does not also stimulate PLC. SKF 83959 and SKF 83822
were given alone and combined with DA D1 and D2 agonists, antagonists, and dextroamphetamine
(AMP).
SKF 83959 acted as a DA D1 agonist (induced oral dyskinesia given alone, counteracted
DA D1 antagonist [NNC 756], induced dystonia, and did not inhibit AMP induced behaviors).
SKF 83822, unlike previously studied DA D1 agonists, did not induce dyskinesia, but
resulted in a state of extreme arousal and locomotor activation without stereotypy,
effectively counteracted by NNC 756, but not by SKF 83959 nor raclopride (DA D2 antagonist).
It is hypothesized that: 1) dyskinesia is linked to PLC stimulation; 2) DA D1 agonism
can play a role in the induction of psychosis, via a mechanism linked neither to AC
nor PLC, and 3) DA D1 antagonists differ in antipsychotic potential, possibly via
this unidentified mechanism.