Contrasting patterns and cellular specificity of transcriptional regulation of the nuclear receptor nerve growth factor-inducible B by haloperidol and clozapine in the rat forebrain.
This study was designed to investigate the possible involvement of members of the nuclear receptor family of transcription factors in the effects of antipsychotic drugs used in the treatment of schizophrenia. We have identified, using RT-PCR screening, an important modulation of nerve growth factor-inducible B (NGFI-B) mRNA levels by typical and atypical neuroleptics in the rat forebrain. NGFI-B, a member of the nuclear receptor family, can be observed in target structures of dopaminergic pathways. Using in situ hybridization, we also demonstrate that typical and atypical antipsychotics induced contrasting patterns of expression of NGFI-B after both acute and chronic administration. An acute treatment with clozapine or haloperidol induces high NGFI-B mRNA levels in the prefrontal and cingulate cortices and in the nucleus accumbens shell. However, haloperidol, but not clozapine, dramatically increases NGFI-B expression in the dorsolateral striatum. In contrast, chronic treatment with clozapine reduces NGFI-B expression below basal levels in the rat forebrain, whereas haloperidol still induces high NGFI-B mRNA levels in the dorsolateral striatum. Finally, using a double in situ hybridization technique, we show that acute administration of both neuroleptics increases NGFI-B expression in neurotensin-containing neurons in the nucleus accumbens shell, whereas the effects of haloperidol in the dorsolateral striatum are mainly observed in enkephalin-containing neurons. These results are the first demonstration that members of the nuclear receptor family of transcription factors could play an important role in the effects of antipsychotic drugs.
Beaudry
G
G
Unité de Neuroscience, Centre de Recherche du Centre Hospitalier Universitaire du Québec, and Département de Médecine, Faculté de Médecine, Université Laval, Québec, Canada.
Langlois
M C
MC
Weppe
I
I
Rouillard
C
C
Lévesque
D
D
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D003024:Clozapine / Q000008:administration & dosage*; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004334:Drug Administration Schedule; D004399:Dynorphins / Q000235:genetics / Q000378:metabolism; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006220:Haloperidol / Q000008:administration & dosage*; D017403:In Situ Hybridization; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009496:Neurotensin / Q000235:genetics / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D009714:Nucleus Accumbens / Q000166:cytology / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis; D011987:Receptors, Steroid; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*
D014150:Antipsychotic Agents; D004268:DNA-Binding Proteins; D004745:Enkephalins; C539820:Nr4a1 protein, rat; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D009496:Neurotensin; D004399:Dynorphins; D003024:Clozapine; D006220:Haloperidol