Differential patterns of induction of NGFI-B, Nor1 and c-fos mRNAs in striatal subregions by haloperidol and clozapine.
Disturbances of retinoid activated transcription mechanisms have recently been implicated as risk factors for schizophrenia. In this study we have compared the regulation of mRNAs for the nuclear orphan receptor NGFI-B, which forms a functional heterodimer with the retinoid x receptor and the related orphan nuclear receptor Nor1 with c-fos mRNA after acute and chronic treatments with haloperidol and clozapine. The antipsychotic drugs haloperidol and clozapine have different clinical profiles. Haloperidol is a typical neuroleptic giving extrapyramidal side effects (EPS), whereas the atypical compound clozapine does not. Acute haloperidol treatment increased NGFI-B, Nor1 and c-fos mRNAs in nucleus accumbens shell and core as well as medial and lateral caudate putamen. In contrast, clozapine lead to an increase of NGFI-B, Nor1 and c-fos only in the accumbens shell. No haloperidol or clozapine effect on these mRNAs was detected in cingulate, sensory or motor cortex. Chronic haloperidol lead to an increase of NGFI-B mRNA in the accumbens core. Acutely, it is possible that the increased levels of NGFI-B, Nor1 and c-fos mRNA levels in striatum and accumbens might indicate a neural activation which possibly can be used when screening for drugs that do not produce EPS. Also, the increased levels of NGFI-B, which is an important component in retinoid signaling, both after acute and chronic treatments of haloperidol suggests altered sensitivity to retinoids which could be an important component for the beneficial antipsychotic effect.
Werme
M
M
Department of Neuroscience, Karolinska Institute, S-171 77, Stockholm, Sweden.
Ringholm
A
A
Olson
L
L
Brené
S
S
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004334:Drug Administration Schedule; D006220:Haloperidol / Q000494:pharmacology*; D017403:In Situ Hybridization; D008297:Male; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D011987:Receptors, Steroid; D012559:Schizophrenia / Q000188:drug therapy / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics*; D014212:Tretinoin / Q000378:metabolism*
D014150:Antipsychotic Agents; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; C539820:Nr4a1 protein, rat; C091333:Nr4a3 protein, rat; D009687:Nuclear Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D017448:Receptors, Dopamine D2; D011987:Receptors, Steroid; D014157:Transcription Factors; D014212:Tretinoin; D003024:Clozapine; D006220:Haloperidol