Clozapine:: Dopamine D1 receptor agonism in the prefrontal cortex as the code to decipher a rosetta stone of antipsychotic drugs

A large number of ligand binding studies have shown that clozapine has a number of receptor affinities, including those of the dopamine (DA) D-1 and D-2 receptor families. The study of intrinsic efficacy at these receptors is less straightforward. In the experiments summarised here, evidence is presented that clozapine behaves as an agonist at DA D-1 receptors. Thus, the hypothermia produced by clozapine (2.5 mg kg(-1)) in the rat is fully antagonised by either of the selective DA D-1 receptor antagonists SCH-23390 (0.1 mg kg(-1)) or NNC-687 (4 mg kg(-1)). These results provide an intriguing explanation for the clinical profile of clozapine as an atypical antipsychotic drug. Thus, there are supporting clinical and laboratory observations implicating DA D-1 receptors in the prefrontal cortex in cognitive functions. Finally, clozapine displays features with regard to extrapyramidal motor mechanisms, and seizure thresholds, that could be explained by its properties as a DA D-1 receptor agonist.