Using an automated PCR-based genomics approach, TOtal Gene expression Analysis (TOGA), we have examined gene expression profiles of mouse striatum and frontal cortex in response to clozapine and haloperidol drug treatment. Of 17 315 mRNAs observed, TOGA identified several groups of related molecules that were regulated by drug treatment. The expression of some genes encoding proteins involved in neurotransmission, signal transduction, oxidative stress, cell adhesion, apoptosis and proteolysis were altered in the brains of both clozapine- and haloperidol-treated mice as recognized by TOGA. Most notable was the differential expression of those genes whose products are associated with lipid metabolism. These include apolipoprotein D (apoD), the mouse homolog of oxysterol-binding protein-like protein 8 (OSBPL8), a diacylglycerol receptor (n-chimerin), and lysophosphatidic acid (LPA) acyltransferase. Real-time PCR analysis confirmed increases in the RNA expression of apoD (1.6-2.2-fold) and OSBPL8 (1.7-2.6-fold), and decreases in the RNA expression of n-chimerin (1.5-2.2-fold) and LPA acyltransferase (1.5-fold) in response to haloperidol and/or clozapine treatment. Additional molecules related to calcium homeostasis and signal transduction, as well as four sequences of previously unidentified mRNAs, were also confirmed by real-time PCR to be regulated by drug treatment. While antipsychotic drugs may affect several metabolic pathways, lipid metabolism/signaling pathways may be of particular importance in the mechanisms of antipsychotic drug action and in the pathophysiology of psychiatric disorders.