Impact of antipsychotic drug administration on the expression of nuclear receptors in the neocortex and striatum of the rat brain.

We have recently shown that the expression of the nerve growth factor-inducible gene B (NGFI-B, or Nur77), a transcription factor belonging to the large ligand-activated nuclear receptor family, is modulated by antipsychotic drugs in the rat forebrain. In the present work, we have investigated the impact of antipsychotic drugs on a series of transcription factors also belonging to the nuclear receptor family. The receptors investigated include retinoid X receptor (RXR), thyroid hormone receptor (TR), retinoic acid receptor (RAR), RAR-related orphan receptor (RZR) and Rev-erb receptor isoforms in addition to the NGFI-B transcript. We have used in situ hybridization to monitor their mRNA levels after acute and chronic antipsychotic drug administration. RZRbeta and NGFI-B mRNA levels are down-regulated after chronic haloperidol or clozapine treatment in the primary somatosensory cortex. The TRbeta1 isoform mainly expressed in the cingulate cortex is modulated only after chronic clozapine treatment, whereas TRalpha isoform mRNAs are modulated by both antipsychotics in the cingulate cortex and nucleus accumbens shell; two brain areas associated with limbic functions. The RXRgamma1 isoform, mostly expressed in the dorsolateral portion of the striatum is modestly affected by antipsychotics. Modulation of the expression of transcription factors belonging to the ligand-activated nuclear receptor family by antipsychotics represents an additional molecular event in the mechanism of action of these drugs. We suggest that modification of the pattern of transcription factor expression may play a role in long-term cellular responses to these drugs.