Clozapine produces potent antidopaminergic effects anatomically specific to the mesolimbic system

Although weak as an antagonist at brain dopamine receptors, clozapine is very strongly antidopaminergic when measured by in vivo single-neuron electrophysiologic recording, in vivo brain microdialysis, in vivo brain voltammetric electrochemistry, in vivo electrical brain stimulation, or in vivo neurobehavioral techniques. Three aspects of clozapine's strong antidopaminergic actions are remarkable. First, clozapine's antidopaminergic potency is stronger than can be explained by its comparatively weak interaction with dopamine receptors, implying that a significant portion of its antidopaminergic action may be transsynaptic and secondary to actions on nondopamine neurotransmitter systems. Second, clozapine's strong antidopaminergic action is seen more reliably with chronic rather than acute administration, implying that some cumulative neurochemical process underlies the gradual recruitment of dopamine blockade. Third, and most remarkably, clozapine's strong antidopaminergic action is anatomically specific-present in the mesolimbic dopamine system but absent in the nigrostriatal dopamine system. This mesolimbic-specific dopamine blockade may underlie at least a portion of clozapine's atypical clinical profile.