Clozapine: Dopamine D1Receptor Agonism in the Prefrontal Cortex as the Code to Decipher a Rosetta Stone of Antipsychotic Drugs

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Abstract
A large number of ligand binding studies have shown that clozapine has a number of receptor affinities, including those of the dopamine (DA) D1and D2receptor 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 D1receptors. Thus, the hypothermia produced by clozapine (2.5 mg kg–1) in the rat is fully antagonised by either of the selective DA D1receptor 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 D1receptors 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 D1receptor agonist.