Haloperidol had the following actions in these volunteers: (i) it increased neuronal activity in the caudate/putamen

(presumably a disinhibition); (ii) it increased neuronal activity in the thalamus (presumably associated with a diminished inhibitory reticulothalamic signal); (iii) it decreased anterior cingulate neuronal activity (presumably secondary to reduced activity in the thalamocortical excitatory afferent pathway); and (iv) it decreased middle frontal cortical activity (ie, Inhibitors,research,lifescience,medical the same explanation as for [iii]).22 The “explanations” (given in parentheses above) represent the interpretation we have made of the functional data to shed light on the question of the neural mechanism of antipsychotic drug action. Wc propose that the disinhibition that haloperidol (or any D2 dopamine receptor antagonist) produces in the caudate/putamen is transmitted through the basal Inhibitors,research,lifescience,medical ganglia and thalamus to ultimately inhibit key areas of the neocortex. These PET findings have been replicated in our laboratory using rCBF,23 and the data are entirely consistent. These results are consistent with many of the functional imaging results from other laboratories doing similar kinds of studies.24,25 Animals Experiments in our laboratory over the last few years have involved the administration

of traditional and new antipsychotic drugs to laboratory rats for subchronic time periods (6 months) for the purpose Inhibitors,research,lifescience,medical of examining critical neurotransmitter systems in the central nervous system (CNS)

regions (the basal ganglia-thalamocortical neural circuit) and their alteration with chronic drug treatment. We postulated that Inhibitors,research,lifescience,medical the neurochemical marker for D2 dopamine receptor blockade (D2 upregulation) and the “transmitted” signals through this system would both vary between the traditional and new drugs. We measured D2 dopamine receptor density in rat caudate, GABAa (GABA: gamma-aminobutyric acid) receptor density and Dj dopamine receptor density in rat substantia nigra, and GABAA Inhibitors,research,lifescience,medical receptor density and glutamic acid decarboxylase (GAD) mRNA expression in rat thalamus. With haloperidol, all these “markers” significantly changed in each region, implying a potent drug action in the caudate/putamen and a strong transmitted signal through next the rest of the basal ganglia to the thalamus and thereafter to the cortex.26 These data are direct evidence from the experimental animal of the idea of a transmitted antipsychotic action through the basal ganglia and the thalamus to the cortex. With the new antipsychotics, these neurochemical changes were milder and not as broad, but research always involved the basal ganglia and the thalamus. While the dopaminergic component of antipsy-chotic drug action is putativcly mediated through these defined neural circuits, other transmitter-specific components of drug action (eg, antiserotonergic or anti- adrenergic) are likely produced directly in the neocortex.